Compounds and methods for inducing chondrogenesis

ABSTRACT

Described herein are compounds and compositions for the amelioration of arthritis or joint injuries by inducing mesenchymal stem cells into chondrocytes.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/794,094, filed Mar. 15, 2013, which is incorporated by referenceherein in its entirety.

FIELD OF INVENTION

The present invention relates to compounds, compositions, preparationsand their use for inducing chondrogenesis and for the treatment ofarthritis or joint injury.

BACKGROUND OF THE INVENTION

Osteoarthritis (OA) represents the most common musculoskeletal disorder.Approximately 40 million Americans are currently affected and thisnumber is predicted to increase to 60 million within the next twentyyears as a result of the aging population and an increase in lifeexpectancy, making it the fourth leading cause of disability. OA ischaracterized by a slow degenerative breakdown of the joint includingboth the articular cartilage (containing the cells and matrix whichproduce lubrication and cushioning for the joint) and the subchondralbone underlying the articular cartilage. Current OA therapies includepain relief with oral NSAIDs or selective cyclooxygenase 2 (COX-2)inhibitors, intra-articular (IA) injection with agents such ascorticorsteroids and hyaluronan, and surgical approaches.

Mesenchymal stem cells (MSCs) are present in adult articular cartilageand upon isolation can be programmed in vitro to undergo differentiationto chondrocytes and other mesenchymal cell lineages. In part it isregulated by growth factors (TGF s, BMPs), serum conditions andcell-cell contact.

SUMMARY OF THE INVENTION

Provided herein is a method of ameliorating arthritis or joint injury ina mammal, the method including administering to a joint of the mammal acomposition having a therapeutically effective amount of a compounddisclosed herein.

Provided herein is a method of inducing differentiation of mesenchymalstem cells into chondrocytes, the method including contactingmesenchymal stem cells with a sufficient amount of a compound disclosedherein, thereby inducing differentiation of the stem cells intochondrocytes.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein:

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴, CH₂CO₂H, CH₂CO₂R⁴, or optionally substituted phenyl;    -   Y is a bond, —(CR⁵R⁶)—, —(CR⁷R⁸)(CR⁹R¹⁰)—, or        —(CR⁷R⁸)(CR⁹R¹⁰)X—;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; provided that        -   a) if Y is a bond and m is 0, then R² is selected from            C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,            (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,            X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,            (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; and            -   R² is not C(O)NH₂, p-CH₂OR⁴, p-CH(OH)CH₂OH, p-CH₂CH₂OH,                or p-CH₂CH₂CH₂OH; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ia, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ib, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   R³ is H;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that if n is 0, then R² is not p-CH₂OR⁴, p-CH₂CH₂OH, or        p-CH₂CH₂CH₂OH.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ic, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   Y is —(CR⁵R⁶)—;    -   C is aryl or heteroaryl;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,        (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,        X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; or R³ together with an adjacent        R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;

-   -   provided that the compound is not

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula I, or a pharmaceutically acceptable salt, solvate,polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomerthereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   v    -   B is CO₂R⁴, CH₂CO₂H, CH₂CO₂R³, or optionally substituted phenyl;    -   Y is a bond, —(CR⁵R⁶)—, —(CR⁷R⁸)(CR⁹R¹⁰)—, or        —(CR⁷R⁸)(CR⁹R¹⁰)X—;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that        -   a) if Y is a bond and m is 0, then R² is selected from            C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,            (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,            X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,            (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; and            -   R² is not C(O)NH₂, p-CH₂OR⁴, p-CH(OH)CH₂OH, p-CH₂CH₂OH,                or p-CH₂CH₂CH₂OH; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ia, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ib, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   R³ is H;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that if n is 4 and R² is not p-CH₂OR⁴, p-CH₂CH₂OH, or        p-CH₂CH₂CH₂OH.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ic, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   Y is —(CR⁵R⁶)—;    -   C is aryl or heteroaryl;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,        (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,        X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴ or R³ together with an adjacent        R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;

-   -   provided that the compound is not

In some embodiments described above or below of a compound of Formula Ior Ia:

-   -   R² is halo, C(O)R⁴, alkyl, optionally substituted alkoxy,        haloalkyl, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        C(O)NR⁴R¹¹, alkyl, or optionally substituted alkoxy;    -   or R³ together with an adjacent R³ or with R² form a ring.

In certain embodiments described above or below of a compound of FormulaI or Ia:

-   -   R² is F, Cl, C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr, OCF₃, OCHF₂,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from CN, F, Cl, C(O)CH₃, CO₂H,        C(O)NH₂, CH₃, OCF₃, or OCH₃;    -   or R³ together with an adjacent R³ or with R² form a ring.        In certain embodiments, R³ is independently selected from CN, F,        Cl, C(O)CH₃, or CO₂H. In certain embodiments, R² is F, Cl,        C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr, OCF₃, or CH₂CH₂CH₂OH.

In some embodiments described above or below of a compound of FormulaIb:

-   -   R² is (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or        C(═NOR⁴)R⁴; and    -   R³ is H.        In certain embodiments, R² is (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, or (CR⁷R⁸)NR⁴SO₂R⁴.        In certain embodiments, R² is CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CHCH₃OH,        CHCH₃CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂CH₂NH₂, CH₂CH₂CHCH₃OH,        C(CH₃)₂CH₂CH₂OH, CH₂CH₂C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂OCH₃, or        OCH₂CH₂NH₂. In certain embodiments, R² is (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹. In        certain embodiments, R² is CH₂C(O)CH₃, CH₂C(O)NH₂,        CH₂CH₂C(O)CH₃, or CH₂CH₂C(O)NH₂.

In some embodiments described above or below of a compound of FormulaIc, C is aryl. In certain embodiments, C is phenyl.

In some embodiments described above or below of a compound of FormulaIc, C is heteroaryl. In certain embodiments, C is pyridinyl,pyrimidinyl, pyridazinyl, or pyrazinyl.

In some embodiments described above or below of a compound of FormulaIc:

-   -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, or        X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from H, CN, halo, CO₂H, or        haloalkyl.

In certain embodiments described above or below of a compound of FormulaIc:

-   -   R² is Cl, F, C(O)CH₃, CO₂H, C(O)NR⁴R¹¹, CH₃, optionally        substituted alkoxy, CF₃, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, or        X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from H, CN, Cl, F, CO₂H, or        CF₃.        In certain embodiments, R² is Cl, F, C(O)CH₃, CO₂H, CH₃, OCH₃,        CF₃; and each R³ is independently selected from H, CN, or CO₂H.        In certain embodiments, R² is CH₂C(O)NH₂, CH₂C(O)CH₃, CH₂C(O)OH,        CH₂CH₂C(O)OH, or CH₂CH₂C(O)NH₂.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula II, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R², NR³C(O)R², NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴,        NR³C(O)NH₂, NR³C(O)NHR², NR³C(O)NR²R⁴, NHC(O)OR², NR³C(O)OR²,        NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is CO₂H, CO₂R³, C(O)NH₂, C(O)NHR², C(O)NR²R⁴, or        SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring;    -   provided that        -   a) if B is NHC(O)R² or NR³C(O)R², then A is not CO₂H; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIa, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NH₂,        NR³C(O)NHR², or NR³C(O)NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is CO₂H or CO₂R³.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIb, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R² or NR³C(O)R²;    -   R² is optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted aralkyl, or optionally substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIc, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   each R³ is independently optionally substituted alkyl or        optionally substituted aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is C(O)NHR² or C(O)NR²R⁴;

-   -   provided that the compound is not CN.

In another aspect provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula II, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R², NR³C(O)R², NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴,        NR³C(O)NH₂, NR³C(O)NHR², NR³C(O)NR²R⁴, NHC(O)OR², NR³C(O)OR²,        NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is CO₂H, CO₂R³, C(O)NH₂, C(O)NHR², C(O)NR²R⁴, or        SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring;    -   provided that        -   a) if B is NHC(O)R² or NR³C(O)R², then A is not CO₂H; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIa, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NH₂,        NR³C(O)NHR², or NR³C(O)NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is CO₂H or CO₂R³.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIb, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R² or NR³C(O)R²;    -   R² is optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted aralkyl, or optionally substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIc, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   each R³ is independently optionally substituted alkyl or        optionally substituted aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is C(O)NHR² or C(O)NR²R⁴;    -   provided that the compound is not CN.

In some embodiments described above or below of a compound of FormulaIIa, B is NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NHR², or NR³C(O)NR²R⁴. Incertain embodiments, B is NHC(O)NHR² or NR³C(O)NHR². In certainembodiments, B is NHC(O)NR²R⁴ or NR³C(O)NR²R⁴. In certain embodiments, Bis NHC(O)NHR².

In some embodiments described above or below of a compound of FormulaIIa, R² is optionally substituted phenyl. In certain embodiments, thephenyl of R² is bisubstituted. In certain embodiments, the phenyl of R²is monosubstituted. In certain embodiments, the phenyl of R² isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH.

In some embodiments described above or below of a compound of FormulaIIb, B is NHC(O)R².

In some embodiments described above or below of a compound of FormulaIIb, B is NR³C(O)R². In certain embodiments, R³ is optionallysubstituted alkyl.

In some embodiments described above or below of a compound of FormulaIIb, each R^(a) and R^(b) is independently optionally substituted alkyl.In some embodiments described above or below of a compound of FormulaIIb, R^(a) and R^(b) together with the N to which they are attached makea ring.

In some embodiments described above or below of a compound of FormulaIIb, R² is optionally substituted phenyl. In certain embodiments, thephenyl of R² is bisubstituted. In certain embodiments, the phenyl of R²is monosubstituted. In certain embodiments, substitution on the phenylof R² is independently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃,CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, or NR³SO₂R⁴. In certainembodiments, B is NHSO₂R³ or NR³SO₂R³. In certain embodiments, B isNHSO₂R³. In certain embodiments, R³ is optionally substituted alkyl. Incertain embodiments, R³ is CH₃. In certain embodiments, B is NHSO₂R⁴ orNR³SO₂R⁴. In certain embodiments, R⁴ is optionally substituted phenyl.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂NH₂, NHSO₂NHR², NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², orNR³SO₂NR²R⁴.

In some embodiments described above or below of a compound of FormulaIIc, A is C(O)NHR². In some embodiments described above or below of acompound of Formula IIc, A is C(O)NR²R⁴. In certain embodiments, R² isoptionally substituted phenyl. In certain embodiments, the phenyl of R²is bisubstituted. In certain embodiments, the phenyl of R² ismonosubstituted. In certain embodiments, substitution on the phenyl ofR² is independently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃,CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula III, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   X is O, NH, or NR⁶;    -   A is C(O), CH₂, or CH—CR³R⁴—C(O)R²;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   R⁶ is optionally substituted phenyl;    -   provided that        -   a) if A is CH—CR³R⁴—C(O)R², then X is O or NH;        -   b) if n is 0, A is CHCH₂C(O)R² and X is O, then R² is

-   -   -    and        -   c) if A is C(O) or CH₂, then X is NR⁶ and R⁶ is not

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIIa, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl; and    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula III, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   X is O, NH, or NR⁶;    -   A is C(O), CH₂, or CH—CR³R⁴—C(O)R²;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   R⁶ is optionally substituted phenyl;    -   provided that        -   a) if A is CH—CR³R⁴—C(O)R², then X is O or NH;        -   b) if n is 0, A is CHCH₂C(O)R² and X is O, then R² is not

-   -   -    and        -   c) if A is C(O) or CH₂, then X is NR⁶ and R⁶ is not

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIIa, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl; and    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴.

In some embodiments described above or below of a compound of FormulaIII, X is NR⁶ and A is C(O). In some embodiments described above orbelow of a compound of Formula III, X is NR⁶ and A is CH₂. In someembodiments described above or below of a compound of Formula III, X isO and A is CH—CR³R⁴—C(O)R². In some embodiments described above or belowof a compound of Formula III, X is NH and A is CH—CR³R⁴—C(O)R².

In some embodiments described above or below of a compound of FormulaIII or IIIa, R³ and R⁴ are both hydrogen. In some embodiments describedabove or below of a compound of Formula III or IIIa, R³ is optionallysubstituted alkyl and R⁴ is hydrogen. In some embodiments describedabove or below of a compound of Formula III or IIIa, R³ and R⁴ areindependently optionally substituted alkyl.

In some embodiments described above or below of a compound of FormulaIII or IIIa, R² is optionally substituted heteroaryl. In certainembodiments, R² is optionally substituted pyridinyl, optionallysubstituted pyrimidinyl, optionally substituted pyridazinyl, oroptionally substituted pyrazinyl.

In some embodiments described above or below of a compound of FormulaIII or IIIa, R² is phenyl. In certain embodiments, the phenyl of R² isbisubstituted. In certain embodiments, the phenyl of R² ismonosubstituted. In certain embodiments, substitution on the phenyl isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH.

In some embodiments described above or below of a compound disclosedherein, B is CO₂R⁴ and R⁴ is optionally substituted alkyl. In someembodiments described above or below of a compound disclosed herein, Bis CO₂R⁴ and R⁴ is hydrogen.

In some embodiments described above or below of a compound disclosedherein, n is 0, 1, or 2. In certain embodiments, n is 0. In certainembodiments, n is 1. In certain embodiments, R¹ is independentlyselected from Cl, F, CH₂OH, CH₂NH₂, OCH₃, OCF₃, OCHF₂, CN, NO₂, CO₂H,and CO₂CH₃.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable salt, solvate,polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomerthereof, selected from:

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound, or a pharmaceutically acceptable salt, solvate, polymorph,prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof,selected from:

In some embodiments described above, the method is performed in vitro.

In some embodiments described above, the method is performed in vivo ina mammal and the stem cells are present in the mammal. In someembodiments, the mammal is a domesticated animal or livestock. Incertain embodiments, the mammal is a human, a dog, a cat, or a horse.

In one aspect, provided herein are compounds of Formula I, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect provided herein are compounds of Formula Ia, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula Ib, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula Ic, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula II, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula IIa, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula IIb, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula IIc, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds of Formula III, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof,selected from:

In another aspect, provided herein are compounds, or pharmaceuticallyacceptable salts, solvates, polymorphs, prodrugs, esters, metabolites,N-oxides, stereoisomers, or isomers thereof, selected from:

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof, and a pharmaceutically acceptableexcipient. In certain embodiments, the pharmaceutical compositionfurther comprises an additional compound which is therapeuticallyeffective for the treatment of arthritis or joint injury and/or thesymptoms associated with arthritis or joint injury in a mammal. Incertain embodiments, the additional compound is selected from NSAIDS,analgesics, angiopoietin-like 3 protein (ANGPTL3) or chondrogenicvariant thereof, oral salmon calcitonin, SD-6010 (iNOS inhibitor),vitamin D3 (choliecalciferol), apoptosis/caspase inhibitors (emricasan),collagen hydrolysate, FGF18, BMP7, avocado soy unsaponifiables (ASU),and hyaluronic acid. In some embodiments, the mammal is human. In otherembodiments, the mammal is a companion animal or livestock. In furtherembodiments, the companion animal or livestock is a dog, cat, or horse.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Osteoarthritis (OA) is characterized by progressive breakdown ofarticular cartilage, and ultimately leads to functional failure ofsynovial joints [Reginster, J. Y. and N. G. Khaltaev, Introduction andWHO perspective on the global burden of musculoskeletal conditions.Rheumatology (Oxford), 2002. 41 Supp 1: p. 1-2]. OA is mediated byseveral pathogenic mechanisms including enzymatic degradation ofextracellular matrix, deficient new matrix formation, cell death, andabnormal activation and hypertrophic differentiation of cartilage cells[Goldring, M. B. and S. R. Goldring, Articular cartilage and subchondralbone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci, 2010.1192(1): p. 230-7]. The only current therapeutic options for OA are painmanagement and surgical intervention [Hunter, D. J., Pharmacologictherapy for osteoarthritis—the era of disease modification. Nat RevRheumatol, 2011. 7(1): p. 13-22].

Mesenchymal stem cells (MSCs), residing in bone marrow and most adulttissues, are capable of self-renewal and differentiation into a varietyof cell lineages including chondrocytes, osteoblasts and adipocytes[Pittenger, M. F., et al., Multilineage potential of adult humanmesenchymal stem cells. Science, 1999. 284(5411): p. 143-7]. Recentstudies found that adult articular cartilage contains MSCs(approximately 3% of the cells) that are capable of multi-lineagedifferentiation. In OA cartilage, the number of these cellsapproximately doubles. These resident stem cells still retain thecapability to differentiate into chondrocytes and thus the capacity torepair the damaged cartilage [Grogan, S. P., et al., Mesenchymalprogenitor cell markers in human articular cartilage: normaldistribution and changes in osteoarthritis. Arthritis Res Ther, 2009.11(3): p. R85; Koelling, S., et al., Migratory chondrogenic progenitorcells from repair tissue during the later stages of humanosteoarthritis. Cell Stem Cell, 2009. 4(4): p. 324-35].

The present invention is based, in part, on the discovery that thecompounds of the present invention stimulate chondrocyte differentiationin mesenchymal stem cells. Accordingly, the present invention providesfor methods of induction of mesenchymal stem cell differentiation intochondrocytes. Further, the present invention provides for administrationof compounds and compositions of the present invention to prevent orameliorate arthritis or joint injury by administrating the compound orcomposition into a joint, the vertebrae, vertebral disc or systemically.

DEFINITIONS

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Oxime” refers to the ═N—OH substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical,which is fully saturated or comprises unsaturations, has from one tothirty carbon atoms, and is attached to the rest of the molecule by asingle bond. Alkyls comprising any number of carbon atoms from 1 to 30are included. An alkyl comprising up to 30 carbon atoms is referred toas a C₁-C₃₀ alkyl, likewise, for example, an alkyl comprising up to 12carbon atoms is a C₁-C₁₂ alkyl. Alkyls (and other moieties definedherein) comprising other numbers of carbon atoms are representedsimilarly. Alkyl groups include, but are not limited to, C₁-C₃₀ alkyl,C₁-C₂₀ alkyl, C₁-C₁₅ alkyl, C₁-C₁₀ alkyl, C₁-C₈ alkyl, C₁-C₆ alkyl,C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈ alkyl andC₄-C₈ alkyl. Representative alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, vinyl, allyl, propynyl, and the like. Alkyl comprisingunsaturations include alkenyl and alkynyl groups. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted as described below.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain, as described for alkyl above. Unless stated otherwisespecifically in the specification, an alkylene group may be optionallysubstituted as described below.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals that are optionally substituted.

“Cycloalkyl” or “carbocycle” refers to a stable, non-aromatic,monocyclic or polycyclic carbocyclic ring, which may include fused orbridged ring systems, which is saturated or unsaturated. Representativecycloalkyls or carbocycles include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms, from three to ten carbonatoms, from three to eight carbon atoms, from three to six carbon atoms,from three to five carbon atoms, or three to four carbon atoms.Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Polycyclic cycloalkyls or carbocycles include, for example, adamantyl,norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane,and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise statedspecifically in the specification, a cycloalkyl or carbocycle group maybe optionally substituted. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, the following moieties:

and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” similarly refers to a radical of the formula —OR_(a) whereR_(a) is a haloalkyl radical as defined. Unless stated otherwisespecifically in the specification, a haloalkoxy group may be optionallysubstituted as described below.

“Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to a stable 3- to 24-membered non-aromatic ringradical comprising 2 to 23 carbon atoms and from one to 8 heteroatomsselected from the group consisting of nitrogen, oxygen, phosphorous andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,12-crown-4,15-crown-5,18-crown-6,21-crown-7, aza-18-crown-6,diaza-18-crown-6, aza-21-crown-7, and diaza-21-crown-7. Unless statedotherwise specifically in the specification, a heterocyclyl group may beoptionally substituted. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like. The term heterocycloalkyl also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

All the above groups may be either substituted or unsubstituted. Theterm “substituted” as used herein means any of the above groups (e.g,alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyland/or heteroaryl) may be further functionalized wherein at least onehydrogen atom is replaced by a bond to a non-hydrogen atom substituent.Unless stated specifically in the specification, a substituted group mayinclude one or more substituents selected from: oxo, amino, —CO₂H,nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl,cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines,alkylarylamines, diarylamines, trialkylammonium (—N⁺R₃), N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilylgroups, perfluoroalkyl or perfluoroalkoxy, for example, trifluoromethylor trifluoromethoxy. “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced by a higher-order bond(e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles. For example, “substituted”includes any of the above groups in which one or more hydrogen atoms arereplaced with —NH₂, —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. In addition, each of the foregoing substituents mayalso be optionally substituted with one or more of the abovesubstituents. Furthermore, any of the above groups may be substituted toinclude one or more internal oxygen, sulfur, or nitrogen atoms. Forexample, an alkyl group may be substituted with one or more internaloxygen atoms to form an ether or polyether group. Similarly, an alkylgroup may be substituted with one or more internal sulfur atoms to forma thioether, disulfide, etc.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition. In other embodiments, treatmentalso includes prophylactic treatment (e.g., administration of acomposition described herein when an individual is suspected to besuffering from a bacterial infection).

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

Methods

Provided herein is a method of ameliorating arthritis or joint injury ina mammal, the method including administering to a joint of the mammal acomposition having a therapeutically effective amount of a compounddisclosed herein.

Provided herein is a method of inducing differentiation of mesenchymalstem cells into chondrocytes, the method including contactingmesenchymal stem cells with a sufficient amount of a compound disclosedherein, thereby inducing differentiation of the stem cells intochondrocytes.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴, CH₂CO₂H, CH₂CO₂R⁴, or optionally substituted phenyl;    -   Y is a bond, —(CR⁵R⁶)—, —(CR⁷R⁸)(CR⁹R¹⁰)—, or        —(CR⁷R⁸)(CR⁹R¹⁰)X—;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that        -   a) if Y is a bond and m is 0, then R² is selected from            C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,            (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,            X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,            (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; and            -   R² is not C(O)NH₂, p-CH₂OR⁴, p-CH(OH)CH₂OH, p-CH₂CH₂OH,                or p-CH₂CH₂CH₂OH; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ia, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ib, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   R³ is H;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that if n is 0, then R² is not p-CH₂OR⁴, p-CH₂CH₂OH, or        p-CH₂CH₂CH₂OH.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula Ic, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

-   -   wherein    -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   Y is —(CR⁵R⁶)—;

C is aryl or heteroaryl;

-   -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,        (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,        X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; or R³ together with an adjacent        R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;

-   -   provided that the compound is not

In another aspect, provided herein is a method of inucinducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula I, or a pharmaceutically acceptable salt, solvate,polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomerthereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴, CH₂CO₂H, CH₂CO₂R³, or optionally substituted phenyl;    -   Y is a bond, —(CR⁵R⁶)—, —(CR⁷R⁸)(CR⁹R¹⁰)—, or        —(CR⁷R⁸)(CR⁹R¹⁰)X—;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that        -   a) if Y is a bond and m is 0, then R² is selected from            C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,            (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,            X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,            X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,            (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; and            -   R² is not C(O)NH₂, p-CH₂OR⁴, p-CH(OH)CH₂OH, p-CH₂CH₂OH,                or p-CH₂CH₂CH₂OH; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ia, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   or R³ together with an adjacent R³ or with R² form a ring;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ib, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   R² is C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   R³ is H;    -   X is O or CR⁵R⁶;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   provided that if n is 4 and R¹ is H, then R² is not p-CH₂OR⁴,        p-CH₂CH₂OH, or p-CH₂CH₂CH₂OH.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula Ic, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   m is 1, 2, 3, or 4;    -   B is CO₂R⁴;    -   Y is —(CR⁵R⁶)—;    -   C is aryl or heteroaryl;    -   X is O or CR⁵R⁶;    -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,        (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,        X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴;    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂H, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴    -   or R³ together with an adjacent R³ or with R² form a ring;    -   each R⁴ is independently selected from H and optionally        substituted alkyl;    -   each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from        H, halo, optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and        optionally substituted alkoxy; and    -   R¹¹ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;

-   -   provided that the compound is not

In some embodiments described above or below of a compound of Formula Ior Ia:

-   -   R² is halo, C(O)R⁴, alkyl, optionally substituted alkoxy,        haloalkyl, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from CN, halo, C(O)R⁴, CO₂H,        C(O)NR⁴R¹¹, alkyl, or optionally substituted alkoxy;    -   or R³ together with an adjacent R³ or with R² form a ring.

In certain embodiments described above or below of a compound of FormulaI or Ia:

-   -   R² is F, Cl, C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr, OCF₃, OCHF₂,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from CN, F, Cl, C(O)CH₃, CO₂H,        C(O)NH₂, CH₃, OCF₃, or OCH₃;    -   or R³ together with an adjacent R³ or with R² form a ring.        In certain embodiments, R³ is independently selected from CN, F,        Cl, C(O)CH₃, or CO₂H. In certain embodiments, R³ is CN or CO₂H.        In certain embodiments, R² is F, Cl, C(O)CH₃, CH₃, CF₃, OCH₃,        OEt, OPr, OCF₃, or CH₂CH₂CH₂OH. In certain embodiments, R² is        CH₂CH₂CH₂OH. In certain embodiments, R³ together with an        adjacent R³ or with R² form a ring.

In certain embodiments, R² is (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and each R³is independently selected from CN, F, Cl, C(O)CH₃, CO₂H, C(O)NH₂, CH₃,OCF₃, or OCH₃. In certain embodiments, R² is F, Cl, C(O)CH₃, CH₃, CF₃,OCH₃, OEt, OPr, OCF₃, or CH₂CH₂CH₂OH; and R³ is independently selectedfrom CN, F, Cl, C(O)CH₃, or CO₂H. In certain embodiments, R² is F, Cl,C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr, OCF₃, or CH₂CH₂CH₂OH; and R³ isindependently selected from CN or CO₂H. In certain embodiments, R² isCH₂CH₂CH₂OH and R³ is independently selected from CN, F, Cl, C(O)CH₃, orCO₂H.

In some embodiments described above or below of a compound of Formula I:

-   -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; and    -   each R³ is independently selected from CN, halo, C(O)R⁴,        C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴.

In some embodiments described above or below of a compound of FormulaIa:

-   -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹,        (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,        (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; and    -   each R³ is independently selected from CN, halo, C(O)R⁴,        C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴,        (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴.

In some embodiments described above or below of a compound of FormulaIb:

-   -   R² is (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,        X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or        C(═NOR⁴)R⁴; and    -   R³ is H.        In certain embodiments, R² is (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, or (CR⁷R⁸)NR⁴SO₂R⁴.        In certain embodiments, R² is CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CHCH₃OH,        CHCH₃CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂CH₂NH₂, CH₂CH₂CHCH₃OH,        C(CH₃)₂CH₂CH₂OH, CH₂CH₂C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂OCH₃, or        OCH₂CH₂NH₂. In certain embodiments, R² is (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹. In        certain embodiments, R² is CH₂C(O)CH₃, CH₂C(O)NH₂,        CH₂CH₂C(O)CH₃, or CH₂CH₂C(O)NH₂.

In some embodiments described above or below of a compound of FormulaIc, C is aryl. In certain embodiments, C is phenyl. In certainembodiments, C is naphthyl.

In some embodiments described above or below of a compound of FormulaIc, C is heteroaryl. In certain embodiments, C is pyridinyl,pyrimidinyl, pyridazinyl, or pyrazinyl. In certain embodiments, C ispyridinyl. In certain embodiments, C is pyrimidinyl. In certainembodiments, C is pyridazinyl. In certain embodiments, C is a 5-memberedheteroaryl ring. In certain embodiments, C is thiophene, benzofuran,pyrrole, thiazole, imidazole, oxazole, pyrazole, or triazole.

In some embodiments described above or below of a compound of FormulaIc:

-   -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,        (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,        (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,        X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; and    -   each R³ is independently selected from H, CN, halo, C(O)R⁴,        CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy,        haloalkyl, SO₂R⁴, (CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴,        X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴,        X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹,        (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴;    -   provided that if n=0 and C is phenyl, R² is not CO₂H or p-OCH₃.

In some embodiments described above or below of a compound of FormulaIc:

-   -   R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally        substituted alkoxy, haloalkyl, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, or        X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from H, CN, halo, CO₂H, or        haloalkyl.

In certain embodiments described above or below of a compound of FormulaIc:

-   -   R² is Cl, F, C(O)CH₃, CO₂H, C(O)NR⁴R¹¹, CH₃, optionally        substituted alkoxy, CF₃, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, or        X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from H, CN, Cl, F, CO₂H, or        CF₃.        In certain embodiments, R² is Cl, F, C(O)CH₃, CO₂H, CH₃, OCH₃,        CF₃; and each R³ is independently selected from H, CN, or CO₂H.        In certain embodiments, R² is CH₂C(O)NH₂, CH₂C(O)CH₃, CH₂C(O)OH,        CH₂CH₂C(O)OH, or CH₂CH₂C(O)NH₂. In certain embodiments, R² is        CO₂H. In certain embodiments, R² is CO₂H and each R³ is        independently selected from H, CN, Cl, F, or CF₃.

In certain embodiments described above or below of a compound of FormulaIc:

-   -   R² is Cl, F, C(O)CH₃, CO₂H, C(O)NR⁴R¹¹, CH₃, optionally        substituted alkoxy, CF₃, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,        (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, or        X(CR⁷R⁸)C(O)NR⁴R¹¹; and    -   each R³ is independently selected from H, CN, or CO₂H.        In certain embodiments, R² is CH₂C(O)NH₂, CH₂C(O)CH₃, CH₂C(O)OH,        CH₂CH₂C(O)OH, or CH₂CH₂C(O)NH₂; and each R³ is independently        selected from H, CN, or CO₂H.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula II, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R², NR³C(O)R², NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴,        NR³C(O)NH₂, NR³C(O)NHR², NR³C(O)NR²R⁴, NHC(O)OR², NR³C(O)OR²,        NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is CO₂H, CO₂R³, C(O)NH₂, C(O)NHR², C(O)NR²R⁴, or        SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring;    -   provided that        -   a) if B is NHC(O)R² or NR³C(O)R², then A is not CO₂H; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIa, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NH₂,        NR³C(O)NHR², or NR³C(O)NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is CO₂H or CO₂R³.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIb, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R² or NR³C(O)R²;    -   R² is optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted aralkyl, or optionally substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIc, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   each R³ is independently optionally substituted alkyl or        optionally substituted aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is C(O)NHR² or C(O)NR²R⁴;

-   -   provided that the compound is not CN.

In another aspect provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula II, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R², NR³C(O)R², NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴,        NR³C(O)NH₂, NR³C(O)NHR², NR³C(O)NR²R⁴, NHC(O)OR², NR³C(O)OR²,        NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is CO₂H, CO₂R³, C(O)NH₂, C(O)NHR², C(O)NR²R⁴, or        SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring;    -   provided that        -   a) if B is NHC(O)R² or NR³C(O)R², then A is not CO₂H; and        -   b) the compound is not selected from

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIa, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)NH₂, NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NH₂,        NR³C(O)NHR², or NR³C(O)NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is CO₂H or CO₂R³.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIb, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHC(O)R² or NR³C(O)R²;    -   R² is optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted aralkyl, or optionally substituted alkyl;    -   R³ is optionally substituted alkyl or optionally substituted        aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴;    -   A is SO₂NR^(a)R^(b); and    -   each R^(a) and R^(b) is independently optionally substituted        alkyl or together with the N to which they are attached make a        ring.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIc, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, NR³SO₂R⁴, NHSO₂NH₂, NHSO₂NHR²,        NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴;    -   each R² and R⁴ is independently optionally substituted phenyl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aralkyl, or optionally        substituted alkyl;    -   each R³ is independently optionally substituted alkyl or        optionally substituted aralkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   A is C(O)NHR² or C(O)NR²R⁴;

-   -   provided that the compound is not CN.

In some embodiments described above or below of a compound of FormulaIIa, B is NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NHR², or NR³C(O)NR²R⁴. Incertain embodiments, B is NHC(O)NHR² or NR³C(O)NHR². In certainembodiments, B is NHC(O)NR²R⁴ or NR³C(O)NR²R⁴. In certain embodiments, Bis NHC(O)NHR².

In some embodiments described above or below of a compound of FormulaIIa, B is NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NHR², or NR³C(O)NR²R⁴; and Ais CO₂H. In certain embodiments, B is NHC(O)NHR² or NR³C(O)NHR²; and Ais CO₂H. In certain embodiments, B is NHC(O)NHR² and A is CO₂H. Incertain embodiments, B is NHC(O)NHR² and A is CO₂H, wherein R² isoptionally substituted phenyl.

In some embodiments described above or below of a compound of FormulaIIa, B is NHC(O)NHR², NHC(O)NR²R⁴, NR³C(O)NHR², or NR³C(O)NR²R⁴; and Ais CO₂R³. In certain embodiments, B is NHC(O)NHR² or NR³C(O)NHR²; and Ais CO₂R³. In certain embodiments, B is NHC(O)NHR² and A is CO₂R³. Incertain embodiments, B is NHC(O)NHR² and A is CO₂R³, wherein R² isoptionally substituted phenyl.

In some embodiments described above or below of a compound of FormulaIIa, R² is optionally substituted phenyl. In certain embodiments, thephenyl of R² is bisubstituted. In certain embodiments, the phenyl of R²is monosubstituted. In certain embodiments, substitution on the phenylof R² is independently selected from optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, halo, CN,CO₂H, amino, monoalkylamine, dialkylamine, monoarylamine,alkylarylamine, cycloalkyl, hydroxy, C(O)-(optionally substitutedalkyl), C(O)NH₂, C(O)NH-(optionally substituted alkyl), alkylthioether,alkylsulfoxide, alkylsulfone, C(O)-(optionally substituted aryl),C(O)NH-(optionally substituted aryl), arylthioether, arylsulfoxide, orarylsulfone. In certain embodiments, substitution on the phenyl of R² isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitutionon the phenyl of R² consists of CN and a group selected from F, Cl,CO₂H, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. Incertain embodiments, bisubstitution on the phenyl of R² consists of CO₂Hand a group selected from F, Cl, CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH,CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitution on thephenyl of R² consists of CH₂CH₂CH₂OH and a group selected from F, Cl,CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CO₂H.

In some embodiments described above or below of a compound of FormulaIIa, R² is optionally substituted naphthyl.

In some embodiments described above or below of a compound of FormulaIIa, R² is optionally substituted heteroaryl. In certain embodiments, R²is optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted pyridazinyl, or optionally substituted pyrazinyl.In certain embodiments, R² is an optionally substituted 5-memberedheteroaryl ring. In certain embodiments, the 5-membered heteroaryl ringis thiophene, benzofuran, pyrrole, thiazole, imidazole, oxazole,pyrazole, or triazole. In certain embodiments, R² is an optionallysubstituted bicyclic heteroaryl. In certain embodiments, the bicyclicheteroaryl is benzimidazole, benzthiazole, benzoxazole, indazole,quinoline, or naphthyridine.

In some embodiments described above or below of a compound of FormulaIIb, B is NHC(O)R². In certain embodiments, B is NHC(O)R² and R² isoptionally substituted phenyl. In certain embodiments, B is NHC(O)R² andR² is optionally substituted heteroaryl.

In some embodiments described above or below of a compound of FormulaIIb, B is NR³C(O)R². In certain embodiments, R³ is optionallysubstituted alkyl.

In some embodiments described above or below of a compound of FormulaIIb, each R^(a) and R^(b) is independently optionally substituted alkyl.In certain embodiments, each R^(a) and R^(b) is independently alkyl. Insome embodiments described above or below of a compound of Formula IIb,R^(a) and R^(b) together with the N to which they are attached make aring. In certain embodiments, the ring is morpholinyl, thiomorpholinyl,piperidinyl, pyrrolidinyl, azetidinyl, aziridinyl, azepanyl,homopiperazinyl, or piperazinyl.

In some embodiments described above or below of a compound of FormulaIIb, R² is optionally substituted phenyl. In certain embodiments, thephenyl of R² is bisubstituted. In certain embodiments, the phenyl of R²is monosubstituted. In certain embodiments, substitution on the phenylof R² is independently selected from optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, halo, CN,CO₂H, amino, monoalkylamine, dialkylamine, monoarylamine,alkylarylamine, cycloalkyl, hydroxy, C(O)-(optionally substitutedalkyl), C(O)NH₂, C(O)NH-(optionally substituted alkyl), alkylthioether,alkylsulfoxide, alkylsulfone, C(O)-(optionally substituted aryl),C(O)NH-(optionally substituted aryl), arylthioether, arylsulfoxide, orarylsulfone. In certain embodiments, substitution on the phenyl of R² isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitutionon the phenyl of R² consists of CN and a group selected from F, Cl,CO₂H, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. Incertain embodiments, bisubstitution on the phenyl of R² consists of CO₂Hand a group selected from F, Cl, CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH,CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitution on thephenyl of R² consists of CH₂CH₂CH₂OH and a group selected from F, Cl,CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CO₂H.

In some embodiments described above or below of a compound of FormulaIIb, R² is optionally substituted naphthyl.

In some embodiments described above or below of a compound of FormulaIIb, R² is optionally substituted heteroaryl. In certain embodiments, R²is optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted pyridazinyl, or optionally substituted pyrazinyl.In certain embodiments, R² is an optionally substituted 5-memberedheteroaryl ring. In certain embodiments, the 5-membered heteroaryl ringis thiophene, benzofuran, pyrrole, thiazole, imidazole, oxazole,pyrazole, or triazole. In certain embodiments, R² is an optionallysubstituted bicyclic heteroaryl. In certain embodiments, the bicyclicheteroaryl is benzimidazole, benzthiazole, benzoxazole, indazole,quinoline, or naphthyridine.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, or NR³SO₂R⁴. In certainembodiments, B is NHSO₂R³ or NR³SO₂R³. In certain embodiments, B isNHSO₂R³. In certain embodiments, R³ is optionally substituted alkyl. Incertain embodiments, R³ is alkyl. In certain embodiments, R³ is CH₃. Incertain embodiments, B is NHSO₂R⁴ or NR³SO₂R⁴. In certain embodiments,R⁴ is optionally substituted phenyl. In certain embodiments, R⁴ isoptionally substituted naphthyl. In certain embodiments, R⁴ isoptionally substituted heteroaryl. In certain embodiments, R⁴ isoptionally substituted heterocyclyl.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, or NR³SO₂R⁴ and A is C(O)NHR². Incertain embodiments, B is NHSO₂R³ or NR³SO₂R³ and A is C(O)NHR². Incertain embodiments, B is NHSO₂R³ and A is C(O)NHR². In certainembodiments, B is NHSO₂R³ and A is C(O)NHR², wherein R³ is optionallysubstituted alkyl. In certain embodiments, B is NHSO₂R³ and A isC(O)NHR², wherein R³ is optionally substituted alkyl and R² isoptionally substituted phenyl. In certain embodiments, B is NHSO₂R³ andA is C(O)NHR², wherein R³ is optionally substituted alkyl and R² isoptionally substituted heteroaryl.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂R³, NR³SO₂R³, NHSO₂R⁴, or NR³SO₂R⁴ and A is C(O)NR²R⁴. Incertain embodiments, B is NHSO₂R³ or NR³SO₂R³ and A is C(O)NR²R⁴. Incertain embodiments, B is NHSO₂R³ and A is C(O)NR²R⁴. In certainembodiments, B is NHSO₂R³ and A is C(O)NR²R⁴, wherein R³ is optionallysubstituted alkyl. In certain embodiments, B is NHSO₂R³ and A isC(O)NR²R⁴, wherein R³ is optionally substituted alkyl and

-   -   R² is optionally substituted phenyl. In certain embodiments, B        is NHSO₂R³ and A is C(O)NR²R⁴, wherein R³ is optionally        substituted alkyl and R² is optionally substituted heteroaryl.

In some embodiments described above or below of a compound of FormulaIIc, B is NHSO₂NH₂, NHSO₂NHR², NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², orNR³SO₂NR²R⁴. In certain embodiments, B is NHSO₂NH₂, NHSO₂NHR²,NHSO₂NR²R⁴, NR³SO₂NH₂, NR³SO₂NHR², or NR³SO₂NR²R⁴ and A is C(O)NHR². Incertain embodiments, B is NHSO₂NH₂, NHSO₂NHR², NHSO₂NR²R⁴, NR³SO₂NH₂,NR³SO₂NHR², or NR³SO₂NR²R⁴ and A is C(O)NR²R⁴.

In some embodiments described above or below of a compound of FormulaIIc, A is C(O)NHR². In some embodiments described above or below of acompound of Formula IIc, A is C(O)NR²R⁴. In certain embodiments, R² isoptionally substituted phenyl. In certain embodiments, the phenyl of R²is bisubstituted. In certain embodiments, the phenyl of R² ismonosubstituted. In certain embodiments, substitution on the phenyl ofR² is independently selected from optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, halo, CN,CO₂H, amino, monoalkylamine, dialkylamine, monoarylamine,alkylarylamine, cycloalkyl, hydroxy, C(O)-(optionally substitutedalkyl), C(O)NH₂, C(O)NH-(optionally substituted alkyl), alkylthioether,alkylsulfoxide, alkylsulfone, C(O)-(optionally substituted aryl),C(O)NH-(optionally substituted aryl), arylthioether, arylsulfoxide, orarylsulfone. In certain embodiments, substitution on the phenyl of R² isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitutionon the phenyl of R² consists of CN and a group selected from F, Cl,CO₂H, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. Incertain embodiments, bisubstitution on the phenyl of R² consists of CO₂Hand a group selected from F, Cl, CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH,CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitution on thephenyl of R² consists of CH₂CH₂CH₂OH and a group selected from F, Cl,CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CO₂H. In certainembodiments, R² is optionally substituted naphthyl.

In some embodiments described above or below of a compound of FormulaIIc, R² is optionally substituted heteroaryl. In certain embodiments, R²is optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted pyridazinyl, or optionally substituted pyrazinyl.In certain embodiments, R² is an optionally substituted 5-memberedheteroaryl ring. In certain embodiments, the 5-membered heteroaryl ringis thiophene, benzofuran, pyrrole, thiazole, imidazole, oxazole,pyrazole, or triazole. In certain embodiments, R² is an optionallysubstituted bicyclic heteroaryl. In certain embodiments, the bicyclicheteroaryl is benzimidazole, benzthiazole, benzoxazole, indazole,quinoline, or naphthyridine.

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula III, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   X is O, NH, or NR⁶;    -   A is C(O), CH₂, or CH—CR³R⁴—C(O)R²;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   R⁶ is optionally substituted phenyl;    -   provided that        -   a) if A is CH—CR³R⁴—C(O)R², then X is O or NH;        -   b) if n is 0, A is CHCH₂C(O)R² and X is O, then R² is not

-   -   -    and        -   c) if A is C(O) or CH₂, then X is NR⁶ and R⁶ is not

In another aspect, provided herein is a method of ameliorating arthritisor joint injury in a mammal, the method comprising administering to ajoint of the mammal a composition comprising a therapeutically effectiveamount of a compound of Formula IIIa, or a pharmaceutically acceptablesalt, solvate, polymorph, prodrug, ester, metabolite, N-oxide,stereoisomer, or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl; and    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴.

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula III, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   X is O, NH, or NR⁶;    -   A is C(O), CH₂, or CH—CR³R⁴—C(O)R²;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl;    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴; and    -   R⁶ is optionally substituted phenyl;    -   provided that        -   d) if A is CH—CR³R⁴—C(O)R², then X is O or NH;        -   e) if n is 0, A is CHCH₂C(O)R² and X is O, then R² is not

-   -   -    and        -   if A is C(O) or CH₂, then X is NR⁶ and R⁶ is not

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound of Formula IIIa, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof:

wherein

-   -   each R¹ is independently halo, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted aryloxy,        CN, NO₂, SR⁴, S(O)R⁴, SO₂R⁴, NHR⁵, NR⁴R⁵, CO₂H, or CO₂R⁴;    -   n is 0, 1, 2, 3, or 4;    -   R² is optionally substituted aryl or optionally substituted        heteroaryl;    -   each R³ and R⁴ is independently H or optionally substituted        alkyl; and    -   R⁵ is H, optionally substituted alkyl, C(O)R⁴, C(O)OR⁴,        C(O)NR⁴R⁴, or SO₂R⁴.

In some embodiments described above or below of a compound of FormulaIII, X is NR⁶ and A is C(O). In some embodiments described above orbelow of a compound of Formula III, X is NR⁶ and A is CH₂. In someembodiments described above or below of a compound of Formula III, X isO and A is CH—CR³R⁴—C(O)R². In some embodiments described above or belowof a compound of Formula III, X is NH and A is CH—CR³R⁴—C(O)R².

In some embodiments described above or below of a compound of FormulaIII or IIIa, R³ and R⁴ are both hydrogen. In some embodiments describedabove or below of a compound of Formula III or IIIa, R³ is optionallysubstituted alkyl and R⁴ is hydrogen. In some embodiments describedabove or below of a compound of Formula III or IIIa, R³ and R⁴ areindependently optionally substituted alkyl.

In some embodiments described above or below of a compound of FormulaIII or IIIa, R² is heteroaryl. In certain embodiments, R² is optionallysubstituted optionally substituted pyridinyl, optionally substitutedpyrimidinyl, optionally substituted pyridazinyl, or optionallysubstituted pyrazinyl. In certain embodiments, R² is 5-memberedheteroaryl. In certain embodiments, the 5-membered heteroaryl isthiophene, benzofuran, pyrrole, thiazole, imidazole, oxazole, pyrazole,or triazole. In certain embodiments, R² is bicyclic heteroaryl. Incertain embodiments, the bicyclic heteroaryl is benzimidazole,benzthiazole, benzoxazole, indazole, quinoline, or naphthyridine.

In some embodiments described above or below of a compound of FormulaIII or IIIa, R² is phenyl. In certain embodiments, the phenyl of R² isbisubstituted. In certain embodiments, the phenyl of R² ismonosubstituted. In certain embodiments, substitution on the phenyl ofR² is independently selected from optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, halo, CN,CO₂H, amino, monoalkylamine, dialkylamine, monoarylamine,alkylarylamine, cycloalkyl, hydroxy, C(O)-(optionally substitutedalkyl), C(O)NH₂, C(O)NH-(optionally substituted alkyl), alkylthioether,alkylsulfoxide, alkylsulfone, C(O)-(optionally substituted aryl),C(O)NH-(optionally substituted aryl), arylthioether, arylsulfoxide, orarylsulfone. In certain embodiments, substitution on the phenyl isindependently selected from F, Cl, CO₂H, CN, OCH₃, C(O)CH₃, CF₃, CH₃,CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitutionon the phenyl of R² consists of CN and a group selected from F, Cl,CO₂H, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CH₂CH₂CH₂OH. Incertain embodiments, bisubstitution on the phenyl of R² consists of CO₂Hand a group selected from F, Cl, CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH,CH₂CH₂OH, and CH₂CH₂CH₂OH. In certain embodiments, bisubstitution on thephenyl of R² consists of CH₂CH₂CH₂OH and a group selected from F, Cl,CN, OCH₃, C(O)CH₃, CF₃, CH₃, CH₂OH, CH₂CH₂OH, and CO₂H.

In some embodiments described above or below of a compound of FormulaIII or IIIa, R² is naphthyl.

In some embodiments described above or below of a compound disclosedherein, B is CO₂R⁴ and R⁴ is optionally substituted alkyl. In someembodiments described above or below of a compound disclosed herein, Bis CO₂R⁴ and R⁴ is hydrogen.

In some embodiments described above or below of a compound disclosedherein, n is 0, 1, or 2. In certain embodiments, n is 0. In certainembodiments, n is 1. In certain embodiments, R¹ is independentlyselected from Cl, F, CH₂OH, CH₂NH₂, OCH₃, OCF₃, OCHF₂, CN, NO₂, CO₂H,and CO₂CH₃.

In some embodiments described above or below of a compound of Formula I,the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIa, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIb, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIc, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaII, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIa, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIb, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIc, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIII, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIa, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIb, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIc, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaII, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIa, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIb, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In some embodiments described above or below of a compound of FormulaIIc, the compound is selected from:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

In one aspect, provided herein is a method of ameliorating arthritis orjoint injury in a mammal, the method comprising administering to a jointof the mammal a composition comprising a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable salt, solvate,polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomerthereof, selected from:

In another aspect, provided herein is a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodcomprising contacting mesenchymal stem cells with a sufficient amount ofa compound, or a pharmaceutically acceptable salt, solvate, polymorph,prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof,selected from:

In some embodiments, the mammal does not have, but is at increased riskfor, arthritis or joint injury.

It is contemplated that the compounds, compositions, and methods of thepresent invention may be used to ameliorate any type of arthritis orjoint injury. It is further contemplated that the compounds,compositions, and methods of the present invention may be used toameliorate various cartilagenous disorders. In some embodiments, thecompounds and compositions of the present invention are administered toprevent arthritis or joint injury, for example where there is a geneticor family history of arthritis or joint injury or prior or during jointsurgery or other circumstances where there is an increased risk ofarthritis or joint injury. Exemplary conditions or disorders to betreated or prevented with the compounds, compositions, and methods ofthe invention, include, but are not limited to systemic rheumatoidarthritis, juvenile chronic arthritis, osteoarthritis, degenerative discdisease, spondyloarthropathies, and systemic sclerosis (scleroderma). Insome embodiments of the invention, the compounds, compositions, andmethods of the present invention may be used to treat osteoarthritis. Insome embodiments, the arthritis can be osteoarthritis, trauma arthritis,degenerative disc disease, dupuytren disease, or tendon disease.

In some embodiments, the compounds, compositions, and methods of thepresent invention provide a method for stimulating chondrocyteproliferation and cartilage production in cartilagenous tissues thathave been damaged due to traumatic injury or chondropathy. Traumaticinjury can include, but is not limited to, blunt trauma to the joint, ordamage to ligaments such as tearing the anterior cruciate ligament,medial collateral ligament, or a meniscal tear. Examples of tissues thatexhibit articulated surfaces, and thus are particularly susceptible totreatment include, but are not limited to, spine, shoulder, elbow,wrist, joints of the fingers, hip, knee, ankle, and the joints of thefeet. Examples of diseases that may benefit from treatment includeosteoarthritis, rheumatoid arthritis, other autoimmune diseases, orosteochondritis dessicans. In addition, cartilage malformation is oftenseen in forms of dwarfism in humans suggesting that the compounds,compositions, and methods would be useful in these patients.

It is contemplated that the compounds, compositions, and methods of thepresent invention may be used to treat a mammal. As used herein a“mammal” refers to any mammal classified as a mammal, including humans,domestic and farm animals, and zoo, sports or pet animals, such ascattle (e.g. cows), horses, dogs, sheep, pigs, rabbits, goats, cats,etc. In some embodiments, the mammal can be a human, a dog, a cat, or ahorse. In some embodiments of the invention, the mammal is a human. Insome embodiments, the mammal is a dog, a cat, or a horse. In someembodiments, the mammal is cattle, sheep, pig, goat, or rabbit. In someembodiments, the mammal is a domesticated animal or livestock. Infurther embodiments, the domesticated animal or livestock is a dog, cat,or horse. In some embodiments, the mammal is a companion animal. As usedherein, “companion animal” refers to dog, cat, rodent, and rabbit. Insome embodiments, the mammal is a companion animal or livestock. In someembodiments, the mammal is livestock.

The compounds of the present invention are also useful for inducingdifferentiation of mesenchymal stem cells (MSCs) into chondrocytes. Insome embodiments, the present invention provides a method of inducingdifferentiation of mesenchymal stem cells into chondrocytes, the methodincluding contacting mesenchymal stem cells with a sufficient amount ofa compound of the present invention, thereby inducing differentiation ofthe stem cells into chondrocytes.

MSCs are multipotent stem cells that can differentiate into severaldifferent types of cells including, but not limited to, osteoblasts,chondrocytes and adipocytes. Differentiation is the process by which aspecialized cell type is formed from a less specialized cell type, forexample, a chondrocyte from a MSC. In some embodiments, the method isperformed in vitro. In some embodiments, the method is performed in vivoin a mammal and the stem cells are present in the mammal. In certainembodiments, the mammal is a human, a dog, a cat, or a horse. In certainembodiments, the mammal is a human. In certain embodiments, the mammalis a dog, a cat, or a horse.

Inducing differentiation of MSCs into chondrocytes can be accomplishedusing any suitable amount of a compound of the present invention. Insome embodiments, the compound of the present invention can be presentin an amount from about 0.1 mg to about 10000 mg, e.g., 1.0 mg to 1000mg, e.g., 10 mg to 500 mg, according to the particular application andpotency of the active component. In some embodiments, the compound ofthe present invention can be present in a concentration of 0.1 μM-100 μMin an intra-articular injection to the knee.

Assays for Identifying Compounds

The compounds of the present invention were identified using a varietyof assays. The initial screen identified compounds that stimulated humanmesenchymal stem cells (hMSCs) to develop into chondrocyte nodules.Additional assays were performed to determine toxicity and specificityof chondrocyte differentiation.

Compounds

Described herein are compounds that induce differentiation ofmesenchymal stem cells into chondrocytes. In some embodiments, thecompounds described herein ameliorate arthritis or joint injury in amammal. In some embodiments, the compounds described herein treatarthritis or joint injury in a mammal.

In one aspect, provided herein are compounds of Formula I, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula Ia, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula Ib, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula Ic, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula II, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula IIa, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula IIb, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula IIc, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds of Formula III, orpharmaceutically acceptable salts, solvates, polymorphs, prodrugs,esters, metabolites, N-oxides, stereoisomers, or isomers thereof.

In another aspect, provided herein are compounds, or pharmaceuticallyacceptable salts, solvates, polymorphs, prodrugs, esters, metabolites,N-oxides, stereoisomers, or isomers thereof, selected from:

Preparation of Compounds

Described herein are compounds for inducing differentiation ofmesenchymal stem cells into chondrocytes and for ameliorating arthritisor joint injury in a mammal, and processes for the preparation of thesecompounds. Also described herein are pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically activemetabolites, and pharmaceutically acceptable prodrugs of such compounds.Pharmaceutical compositions comprising at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, and a pharmaceutically acceptable excipientare also provided.

Compounds described herein may be synthesized using standard syntheticreactions known to those of skill in the art or using methods known inthe art. The reactions can be employed in a linear sequence to providethe compounds or they may be used to synthesize fragments which aresubsequently joined by the methods known in the art.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations

(VCH Publishers Inc., 1989). (all of which are incorporated by referencein their entirety). Other methods for the synthesis of compoundsdescribed herein may be found in International Patent Publication No. WO01/01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10(2000) 2167-2170; Burchat et al. Bioorganic & Medicinal ChemistryLetters 12 (2002) 1687-1690. General methods for the preparation ofcompound as disclosed herein may be derived from known reactions in thefield, and the reactions may be modified by the use of appropriatereagents and conditions, as would be recognized by the skilled person,for the introduction of the various moieties found in the formulae asprovided herein.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

Further Forms of Compounds Disclosed Herein Isomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, compounds exist astautomers. The compounds described herein include all possible tautomerswithin the formulas described herein. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S confirguration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and the metabolites,pharmaceutically acceptable salts, esters, prodrugs, solvate, hydratesor derivatives thereof which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention.Certain isotopically-labeled compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³Hand carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereofis prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Polymorphs

In some embodiments, the compounds described herein exist as polymorphs.The invention provides for methods of treating diseases by administeringsuch polymorphs. The invention further provides for methods of treatingdiseases by administering such polymorphs as pharmaceuticalcompositions.

Thus, the compounds described herein include all their crystallineforms, known as polymorphs. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound. Incertain instances, polymorphs have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. In certaininstances, various factors such as the recrystallization solvent, rateof crystallization, and storage temperature cause a single crystal formto dominate.

Prodrugs

In some embodiments, the compounds described herein exist in prodrugform. The invention provides for methods of treating diseases byadministering such prodrugs. The invention further provides for methodsof treating diseases by administering such prodrugs as pharmaceuticalcompositions.

Prodrugs are generally drug precursors that, following administration toan individual and subsequent absorption, are converted to an active, ora more active species via some process, such as conversion by ametabolic pathway. Some prodrugs have a chemical group present on theprodrug that renders it less active and/or confers solubility or someother property to the drug. Once the chemical group has been cleavedand/or modified from the prodrug the active drug is generated. Prodrugsare often useful because, in some situations, they are easier toadminister than the parent drug. They are, for instance, bioavailable byoral administration whereas the parent is not. In certain insatnces, theprodrug also has improved solubility in pharmaceutical compositions overthe parent drug. An example, without limitation, of a prodrug would be acompound as described herein which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyamino acid) bonded to an acidgroup where the peptide is metabolized to reveal the active moiety.

(See for example Bundgaard, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development, Krosgaard-Larsen and Bundgaard,Ed., 1991, Chapter 5, 113-191, which is incorporated herein byreference).

In some embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. The design ofprodrugs to date has been toincrease the effective water solubility of the therapeutic compound fortargeting to regions where water is the principal solvent.

In some embodiments, prodrugs are C₁-C₆ alkyl esters of the compoundsdisclosed herein.

Additionally, prodrug derivatives of compounds described herein can beprepared by methods described herein are otherwise known in the art (forfurther details see Saulnier et al., Bioorganic and Medicinal ChemistryLetters, 1994, 4, 1985). By way of example only, appropriate prodrugscan be prepared by reacting a non-derivatized compound with a suitablecarbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds are prodrugs for another derivative or activecompound.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e.g., two, three or four)nucleic acid residues is covalently joined to a compound of the presentinvention.

Pharmaceutically acceptable prodrugs of the compounds described hereinalso include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts andsulfonate esters. Compounds having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. In certaininstances, all of these prodrug moieties incorporate groups includingbut not limited to ether, amine and carboxylic acid functionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters and disulfide containingesters; ethers, amides, carbamates, hemisuccinates,dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, can reduce,minimize or eliminate this metabolic pathway.

Metabolites

In some embodiments, compounds described herein are susceptible tovarious metabolic reactions. Therefore, in some embodiments,incorporation of appropriate substituents into the structure willreduce, minimize, or eliminate a metabolic pathway. In specificembodiments, the appropriate substituent to decrease or eliminate thesusceptibility of an aromatic ring to metabolic reactions is, by way ofexample only, a halogen, or an alkyl group.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Pharmaceutical Compositions/Formulations

In another aspect, provided herein are pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, and apharmaceutically acceptable excipient.

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

Provided herein are pharmaceutical compositions that include a compoundas described herein and at least one pharmaceutically acceptableinactive ingredient. In some embodiments, the compounds described hereinare administered as pharmaceutical compositions in which a compounddescribed herein is mixed with other active ingredients, as incombination therapy. In other embodiments, the pharmaceuticalcompositions include other medicinal or pharmaceutical agents, carriers,adjuvants, preserving, stabilizing, wetting or emulsifying agents,solution promoters, salts for regulating the osmotic pressure, and/orbuffers. In yet other embodiments, the pharmaceutical compositionsinclude other therapeutically valuable substances.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components (i.e.pharmaceutically acceptable inactive ingredients), such as carriers,excipients, binders, filling agents, suspending agents, flavoringagents, sweetening agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombination thereof. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. In some embodiments, the mammal is a human, a dog, a cat, or ahorse. In some embodiments, the mammal is a human. In some embodiments,the mammal is a dog, a cat, or a horse. A therapeutically effectiveamount can vary widely depending on the severity of the disease, the ageand relative health of the subject, the potency of the compound used andother factors. The compounds can be used singly or in combination withone or more therapeutic agents as components of mixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular,intra-articular), intranasal, buccal, topical, rectal, or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions, liquids,gels, syrups, elixirs, slurries, suspensions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, solidoral dosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,powders, dragees, effervescent formulations, lyophilized formulations,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound described herein aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compounddescribed herein as an active ingredient in free-acid or free-base form,or in a pharmaceutically acceptable salt form. In addition, the methodsand pharmaceutical compositions described herein include the use ofN-oxides (if appropriate), crystalline forms, amorphous phases, as wellas active metabolites of these compounds having the same type ofactivity. In some embodiments, compounds described herein exist inunsolvated form or in solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Pharmaceutical preparations for oral use are obtained by mixing one ormore solid excipient with one or more of the compounds described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active compound doses.

Pharmaceutical preparations that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds are dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Combination Treatment

The compounds and compositions of the present invention can be used incombination with other components suitable for ameliorating arthritis orjoint injury. In some embodiments, the composition can further comprisean additional compound which is therapeutically effective for thetreatment of arthritis or joint injury and/or the symptoms associatedwith arthritis or joint injury in a mammal. In some embodiments, thecomposition can also include a non-steroidal anti-inflammatory drug(NSAID), an analgesic, a glucocorticoid, an angiopoietin-like 3 protein(ANGPTL3) or chondrogenic variant thereof, oral salmon calcitonin,SD-6010 (iNOS inhibitor), vitamin D3 (choliecalciferol), collagenhydrolyzate, FGF18, BMP7, avocado soy unsaponifiables (ASU) orhyaluronic acid. ANGPTL3 is described in more detail in WO201 1/008773(incorporated herein in its entirety). In some embodiments, thecomposition includes an agent with anti-inflammatory activity. In someembodiments, the composition includes an apoptosis modulator. In certainembodiments, the apoptosis modulator is a caspase inhibitor. Onenon-limiting example of an apoptosis/caspase inhibitor is emricasan. Insome embodiments, the composition includesan iNOS inhibitor. Onenon-limiting example of an iNOS inhibitor is SD-6010.

NSAIDS include, but are not limited to, aspirin, diflunisal, salsalate,ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen,dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin,tolmetin, sulindac, etodolac, ketorolac, nabumetone, diclofenac,piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam,mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid,celecoxib, parecoxib, etoricoxib, lumiracoxib, and firocoxib.

Analgesics include, but are not limited to, acetaminophen and opioids(narcotics). Opioids include, but are not limited to,dextropropoxyphene, codeine, tramadol, tapentadol, anileridine,alphaprodine, pethidine, hydrocodone, morphine, oxycodone, methadone,diamorphine, hydromorphone, oxymorphone, levorphanol,7-hydroxymitragynine, buprenorphine, fentanyl, sufentanil, bromadol,etorphine, dihydroetorphine, and carfentanil.

Glucocorticoids include, but are not limited to, hydrocortisone,cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone,betamethasone, triamcinolone, beclometasone, or fludrocortisones.

The compounds described herein may be used in combination with one ormore compounds which are therapeutically effective for the treatment ofarthritis or joint injury and/or the symptoms associated with arthritisor joint injury. Such additional compounds may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a compound disclosed herein. When a compound disclosedherein is used contemporaneously with one or more such additionalcompounds, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention is preferred.However, the combination therapy may also include therapies in which thecompound disclosed herein and one or more additional compounds areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more additional compounds, thecompounds may be used in lower doses than when each is used singly.

The above combinations include combinations of a compound disclosedherein not only with one compound which is therapeutically effective forthe treatment of arthritis or joint injury and/or the symptomsassociated with arthritis or joint injury, but also with two or moresuch compounds. Likewise, compounds disclosed herein, either incombination with a compound which is therapeutically effective for thetreatment of arthritis or joint injury and/or the symptoms associatedwith arthritis or joint injury or by themselves, may be used incombination with other drugs that are used in the prevention, treatment,control, or amelioration of osteoarthritis or joint injury or conditionsassociated with osteoarthritis or joint injury. Such other drugs may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound disclosed herein. Whena compound disclosed herein is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventionalso include those that also contain one or more other activeingredients, in addition to a compound disclosed herein. The weightratio of the compound disclosed herein to the second active ingredientmay be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.

Administration of Pharmaceutical Composition

Suitable routes of administration include, but are not limited to, oral,intravenous, intra-articular, rectal, aerosol, parenteral, ophthalmic,pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, intra-articular, and intranasalinjections.

In some embodiments, compounds disclosed herein and compositions thereofare administered in any suitable manner. The manner of administrationcan be chosen based on, for example, whether local or systemic treatmentis desired, and on the area to be treated. For example, the compositionscan be administered orally, parenterally (e.g., intravenous,subcutaneous, intraperitoneal, intra-articular, or intramuscularinjection), by inhalation, extracorporeally, topically (includingtransdermally, ophthalmically, vaginally, rectally, intranasally) or thelike. In some embodiments, the compositions can be administered bymicroneedle. In some embodiments, the compositions can be administeredby a microneedle array in the form of a patch which can performintracutaneous drug delivery. In some embodiments, the compositions canbe administered by transdermal microneedle patch delivery.

Parenteral administration of the composition, if used, is generallycharacterized by injection. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution of suspension in liquid prior to injection, or asemulsions. A more recently revised approach for parenteraladministration involves use of a slow release or sustained releasesystem such that a constant dosage is maintained.

EXAMPLES List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

-   -   ACN acetonitrile    -   Bn benzyl    -   BOC or Boc tert-butyl carbamate    -   BOP benzotriazol-1-yl-oxytris (dimethylamino) phosphonium t-Bu        tert-butyl    -   Cbz benzyl carbamate    -   Cy Cyclohexyl    -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene    -   DCC dicyclohexylcarbodiimide    -   DCM dichloromethane (CH₂Cl₂)    -   DIC 1,3-diisopropylcarbodiimide    -   DEAD diethyl azodicarboxylate    -   DIAD diisopropyl azodicarboxylate    -   DIPEA diisopropylethylamine    -   DMAP 4-(N,N-dimethylamino)pyridine    -   DMP reagent Dess-Martin Periodinane reagent    -   DMF dimethylformamide    -   DMA N,N-Dimethylacetamide    -   DME 1,2-Dimethoxy-ethane    -   DMSO dimethylsulfoxide    -   Dppf 1,1′-Bis(diphenylphosphino)ferrocene    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl    -   eq equivalent(s)    -   Et ethyl    -   Et₂O diethyl ether    -   EtOH ethanol    -   EtOAc ethyl acetate    -   HOAt 1-hydroxy-7-azabenzotriazole    -   HOBT 1-hydroxybenztriazole    -   HOSu N-hydroxysuccinamide    -   HPLC high performance liquid chromatography    -   LAH lithium aluminum anhydride    -   Me methyl    -   MeI methyliodide    -   MeOH methanol    -   MOMCl methoxymethylchloride    -   MOM methoxymethyl    -   MS mass spectroscopy    -   NMP N-methyl-pyrrolidin-2-one    -   NMR nuclear magnetic resonance    -   PyBOP benzotriazole-1-yl-oxytris-pyrrolidino-phosphonium        Hexafluorophosphate    -   SPHOS 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl    -   TBD 1,5,7-triazabicyclo[4.4.0]-dec-5-ene    -   RP-HPLC reverse phase-high pressure liquid chromatography    -   TBS tert-butyldimethylsilyl    -   TBSCl tert-butyldimethylsilyl chloride    -   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    -   TEOC 2-Trimethylsilylethyl Carbamate    -   TFA trifluoroacetic acid    -   Tf₂O triflate anhydride    -   TMG 1,1,3,3-Tetramethylguanidine    -   THF tetrahydrofuran    -   THP tetrahydropyran    -   TLC thin layer chromatography    -   XPHOS 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Examples for the Preparation of Compounds of the Invention

The starting materials and intermediates for the compounds of thisinvention may be prepared by the application or adaptation of themethods described below, their obvious chemical equivalents, or, forexample, as described in literature such as The Science of Synthesis,Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers(2001-2008). Details of reagent and reaction options are also availableby structure and reaction searches using commercial computer searchengines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com).

SYNTHETIC EXAMPLES

The following preparations of compounds disclosed herein andintermediates are given to enable those of skill in the art to moreclearly understand and to practice the present invention. They shouldnot be considered as limiting the scope of the invention, but merely asillustrative and representative thereof.

To a solution of phthalic anhydride (1.0 eq) in EtOAc was added3-amino-4-chlorobenzonitrile (1 eq), then was stirred for 1-8 h at20-30° C. TLC indicated starting material had disappeared. The reactionmixture was filtered and the solid was purified by recrystallization inEtOAc to afford compound I (12 mg). Final product 1 was confirmed by ¹HNMR and LCMS. LCMS: Found 301.0 [M+H]. ¹H NMR (400 MHz, MeOD-d₄): 8.35(s, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.71 (dd, J=8.0, 4.1 Hz, 1H), 7.67 (d,J=8.4 Hz, 1H), 7.61 (t, J=7.4 Hz. 2H), 7.57 (dd, J=8.4, 2.0 Hz, 1H).

Select compounds in Table 1 were obtained using analogous conditions asthe reaction scheme given above, substituting3-amino-4-chlorobenzonitrile with the appropriate aniline or amine.Reaction yields based on isolated products ranged from 20% to 80%.

To a solution of 4-aminobenzenesulfonamide (100 mg, 0.58 mmol) in AcOH(20 mL), phthalic anhydride (82 mg, 0.55 mmol) was added. The mixturewas stirred at 130° C. for 3 h. The mixture was diluted with H₂O (30 mL)and stirred for 2 h. After filtration to get compound 15 (44 mg, yield:26%) as a white solid. Final product 15 was confirmed by ¹H NMR andLCMS. LCMS: Found 303.0 [M+H]. ¹H NMR (400 MHz, DMSO-d₆): 7.10-7.36 (m,6H), 6.56-6.70 (m, 2H), 6.62 (br s, 2H).

Select compounds in Table 1 were obtained using analogous conditions asthe reaction scheme given above, substituting 4-aminobenzenesulfonamidewith the appropriate aniline. In the case of compound 33, reaction timewas 3 h and the reaction mixture was diluted with H₂O and stirred for 12h for crystallization.

To a solution of compound 15 (276 mg, 0.913 mmol) in AcOH (5 mL), Zn(596.91 mg, 9.13 mmol) and DMF (0.1 mL) were added. The mixture wasstirred at 130° C. for 3 h, then cooled to room temperature andconcentrated to get the crude products as colorless oil. The residue waspurified by prep-HPLC (0.1% TFA as additive), most CH₃CN was removed byevaporation under reduced pressure, and the remaining solvent wasremoved by lyophilization to afford compound 26 (80 mg, yield: 30%) as awhite solid. LCMS: Found 289.1 [M+H].

Compound 27 (Table 1) was obtained using analogous conditions as thereaction scheme given above. In the preparation of compound 27, DMF wasnot used.

The starting material of product 27 was made by the following procedure.

Preparation of Compound 27-2

To a solution of compound 27-1 (3.8 g, 17 mmol) in DCM (50 ml), MeNH₂(5.3 g, 51 mmol) in alcohol was added. The mixture was stirred at roomtemperature for 2 h. The mixture was diluted by DCM (30 ml) and washedwith H₂O (30 ml). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to afford compound 27-2 (3.3 g, yield: 90%).

Preparation of Compound 27-3

To a solution of compound 27-2 (3.3 g, 15.3 mol) in CH₃OH (50 mL) wasadded Pd/C (0.16 g) at room temperature. The mixture was stirred underH₂ (30 psi) at room temperature for 12 h. The mixture was filtered andthe solvent was removed to give the compound 27-3 (2.3 g, yield: 80%) asa gray solid.

Preparation of Starting Material of Compound 27

To a solution of 27-3 (0.5 g, 2.68 mmol) in AcOH (40 mL) was added 27-4(0.433 g, 2.92 mmol). The reaction mixture was stirred at 130° C. for 3h. The reaction mixture was cooled down, and the solvent was removed toafford crude product which was used directly in the next step.

To a solution of the starting material for compound 27 (1.0 g, 3.16mmol) in CH₃OH (20 mL) at 0° C. was added NaBH₄ (239 mg, 6.32 mmol). Themixture was stirred at 0° C. for 15 min before the solvent was removedunder reduced pressure. Water (20 mL) and sat'd. aq. NH₄Cl (20 mL) wasadded to the crude residue. The mixture was stirred for 30 min at roomtemperature. Filtration provided compound 177 (840 mg, yield: 83%) as anoff-white solid.

To a solution of ketone sm-1 (1.0 eq) in dioxane (V/M=10:1) was addedcarboxybenzaldehyde sm-2 (1.2 eq), followed by Sc(OTf)₄. The mixtureheated to reflux for 12 h. Upon cooling to room temperature, the mixturewas concentrated and purified by prep-HPLC to afford compound C.

Select compounds in Table 1 were obtained using Synthetic Scheme C.Reaction yields based on isolated products ranged from 5% to 50%.

To a solution of ketone sm-1 (1.0 eq) in dioxane (V/M=15:1) was addedcarboxybenzaldehyde sm-2 (1.2 eq), followed by Sc(OTf)₄ (2 eq). Themixture was heated to reflux for 12 h. NH₄OAc (5 eq) was added, and thereaction mixture was heated to reflux for an additional 12 h. Uponcooling to room temperature, the mixture was concentrated and purifiedby prep-HPLC to afford compound D.

Select compounds in Table 1 were obtained using Synthetic Scheme D.Reaction yields based on isolated products ranged from 3% to 20%.

To a solution of 2-aminobenzoic acid sm-4 (1 eq) in 2 M NaHCO₃ (V=10 eq)was added sulfonyl chloride sm-3 (1.0 eq), and the mixture was stirredat room temperature for 2 h. TLC indicated starting material haddisappeared. The mixture was extracted with EtOAc. The organic layer wasdried over anhydrous Na₂SO₄, concentrated and purified by pre-HPLC toafford pure product E.

Compound 53 (Table 1) was obtained using Synthetic Scheme E. Reactionyields based on isolated product ranged from 60% to 80%.

To a solution of benzoic acid sm-6 (1 eq) in DMF (10 eq) was added EDCI(1.5 eq) and HOBT (1.5 eq) at 0° C. prior to stirring at roomtemperature for about 2 h. Amine sm-5 (1.5 eq) was added to the reactionmixture, which was stirred at room temperature for an additional 12 h.Water was added, and the mixture was extracted with EtOAc, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography to give the product F.

Select compounds in Table 1 were obtained using Synthetic Scheme F.Reaction yields based on isolated products ranged from 20% to 40%.

4-Cyanobenzoyl chloride (1.0 eq) was added to a solution of2-amino-N,N-dimethylbenzenesulfonamide (1.0 eq) and TEA (1.5 eq) in DCM.The reaction mixture was stirred at 29° C. for about 2 h. TLC indicatedstarting material had disappeared. The reaction mixture was quenchedwith sat'd. aq. NaHCO₃, extracted with DCM, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by prep-HPLC to affordcompound 56 (yield: 70%). LCMS: Found 330.1 [M+H].

Compound 62 (Table 1) was obtained using analogous conditions as thereaction scheme given above. Reaction yields based on isolated productsranged from 70% to 80%.

The requisite aniline starting material I of compounds 56 and 62 weremade by the following procedure.

Preparation of Intermediates Sm-8

A solution of 2-nitrobenzene-1-sulfonyl chloride (1.0 eq) and amine sm-7(1.0 eq) in DCM was stirred at 30° C. for about 2 h. TLC indicatedstarting material had disappeared. The reaction mixture was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated to affordintermediate sm-8 (yield: 72-91%).

Preparation of Aniline Starting Materials I

To a solution of intermediate sm-8 (1.0 eq) in MeOH was added Pd/C. Thereaction mixture was stirred at 50° C. under 50 psi of H₂ for 7 h. TLCindicated starting material had disappeared. The mixture was filtered,and the filtrate was concentrated to afford compound I (yield: 89˜91%).

To a solution of amide sm-10 (1 eq) in THF (V=10 eq) was added dropwiseLiHMDS(1 eq) at 0° C. After 30 min, sulfonyl chloride sm-9 (1.0 eq) wasadded, and the mixture was stirred at room temperature for 2 h. TLCindicated starting material had disappeared. The mixture was extractedwith EtOAc. The organic layer was dried over anhydrous Na₂SO₄,concentrated and purified by pre-HPLC to afford compound H.

Select compounds in Table 1 were obtained using Synthetic Scheme H.Reaction yields based on isolated products ranged from 50% to 80%.

To a stirring mixture of 2-bromo-N-(4-cyanophenyl)benzamide (1.66 mmol)and boronic acid sm-11 (3.32 mmol) in dioxane (10 mL) was added K₃PO₄(1.06 g, 4.98 mmol). Pd₂(dba)₃ (45.61 mg, 49.81 umol) and X-Phos (39.58mg, 83.02 umol) were added under N₂. Finally the mixture was heated to110° C. and stirred for 12 h. After filtration, the mixture wasconcentrated to give intermediate sm-12 as a brown oil. To a solution ofsm-12 (770 mg, 2.16 mmol) in THF (30 mL) was added LiOH (4.32 mL, 4.32mmol) drop-wise and stirred for 12 h. The solution was acidified to pH 4at 10° C., extracted with EtOAc (30 mL), washed with H₂O (50 mL) andbrine (50 mL), concentrated and purified by prep-HPLC (0.1% TFA asadditive). Solvents were removed by evaporation under reduced pressureand lyophilization to afford compound I as a white solid.

Select compounds in Table 1 were obtained using Synthetic Scheme I.Reaction yields based on isolated products ranged from 15% to 30%.

2-Bromo-N-(4-cyanophenyl)benzamide was prepared by the followingprocedure.

A solution of 2-bromobenzoic acid (4.4 g, 21.89 mmol) in SOCl₂ (45 mL)was heated to 70° C. for 2 h. It was evaporated to obtain 2-bromobenzoylchloride as a yellow oil, which was diluted with DCM (90 mL). Theresultant mixture was added drop-wise to a solution of4-aminobenzonitrile (2.59 g, 21.92 mmol) in DCM (10 mL) and Et₃N (4.43g, 43.78 mmol) at 10° C. Finally the mixture was warmed to 30° C. andstirred for 12 h. The mixture was diluted with DCM (100 mL), and washedwith HCl (100 mL), NaHCO₃ (50 mL), H₂O (50 mL) and brine (50 mL). Theorganic layer was dried over Na₂SO₄, concentrated, and purified bysilica gel column chromatography (PE:EtOAc=5:1) to provide2-bromo-N-(4-cyanophenyl)benzamide (4.7 g, yield: 72%) as a white solid.

To a solution of 2-(morpholinosulfonyl)aniline (1.0 eq) in DMF was addedcarboxylic acid sm-13 (1.0 eq), DIPEA (1.5 eq) and HATU (1.3 eq). Theresultant mixture was stirred at 10-15° C. for 16-24 h. TLC indicatedstarting material had disappeared. The reaction mixture was concentratedand the solid was purified by silica gel column chromatography to affordcompound J.

Select compounds in Table 1 were obtained using Synthetic Scheme J.

Methyl 2-isocyanatobenzoate (200 mg 1.13 mmol) and1-(3-aminophenyl)ethanone (167 mg, 1.24 mmol) were dissolved in THF (2.5ml) and heated using microwave heating at 100° C. for 15 min. Thereaction mixture was washed with sat'd. aq. NaHCO₃ and purified viacolumn chromatography (EtOAc:hexanes) to provide the final product 193(262 mg, yield: 75%), which was confirmed by ¹H NMR and LCMS.

Select compounds in Table 1 were obtained using analogous conditions asthe reaction scheme given above. In these reactions, DIPEA was usedinstead of TEA and the temperature was increased to 120° C. Reactionyields based on isolated products ranged from 47-90%.

Compound 195 was dissolved in THF (2 mL) and 1 N NaOH (1 mL). Thereaction mixture was stirred at room temperature for 15 h. The mixturewas diluted with EtOAc (20 mL) prior to the drop-wise addition of 1 NHCl (3 mL) with constant stirring. The organic layer was extracted,dried, and concentrated. The crude product was recrystallized from EtOActo provide compound 196 (25 mg).

Select compounds in Table 1 were obtained using analogous conditions asthe reaction scheme given above. Reaction yields based on isolatedproducts ranged from 80-90%.

To a solution of 2-(methylsulfonamido)benzoic acid (1.0 eq) in DMF wasadded sm-14 (1.0 eq), DIPEA (1.5 eq) and HATU (1.3 eq). The mixture wasstirred at 10-15° C. for 16-24 h. Upon reaction completion as indicatedby TLC, the reaction mixture was concentrated, and the solid waspurified by silica gel chromatography to afford compound L.

Select compounds in Table 1 were obtained using Synthetic Scheme L.

A solution of compound I (320 g, 1.1 mmol) in EtOH (10 mL) was addeddropwisely NaOEt (571.6 mg, 8.4 mmol) at 0° C. for 3 h. The reaction wasacidific with 1N HCl and removed the solvent to get the crude product.The residue was purified by pre-HPLC (0.1% TFA as additive), most CH₃CNwas removed by evaporation under reduced pressure, and the remainedsolvent was removed by hyophilization to afford the compound 28 (17 mg,6% yield) as white solid. LCMS: Found 255.0 [M+H]. ¹H NMR (400 MHz,CDCl₃): 7.50-7.72 (m, 4H), 4.85 (br s, 1H), 3.90 (t, 2H, J=7.2 Hz),2.53-2.72 (m, 5H), 2.14-2.28 (m, 2H).

The intermediate sm-15 was made by the following procedure.

To a solution of 4-amino-N-methylbenzenesulfonamide (200 mg, 1.1 mmol)and Na₂HPO₄ (300 mg, 2.2 mmol) in CHCl₃ (10 mL) was added4-chlorobutanoyl chloride (151 mg, 1.1 mol) drop-wise at 0° C. Afterreagent addition, the mixture was allowed to stir at room temperature.The mixture was concentrated to give crude sm-15, which was useddirectly in the next step without further purification.

A solution of 2-(4-aminophenyl)ethanol (300 mg, 2.2 mmol),isochroman-1,3-dione (355 mg, 2.2 mmol) and KAl(SO₄)₂-12H₂O (522 mg, 11mmol) in MeCN (10 mL) was stirred at room temperature for 1-1.5 h. Thesolvent was removed to obtain crude product. The residue was purified byprep-HPLC (0.1% TFA as additive). Solvents were removed by evaporationunder reduced pressure and lyophilization to afford compound 47 (25 mg,5.5% yield) as a white solid. LCMS: Found 300.1 [M+H].

BIOLOGICAL EXAMPLES Example 1 Human Chondrocyte Differentiation Assay

Human MSCs (50,000) were plated into each well of a 96-well plate andcultured overnight. Compounds (in DMSO solution) were added to the cellsat a final concentration of 1 μM, and the cells were cultured for 7 daysat 5% CO₂, 37° C. The cells were fixed with 10% formalin solution atroom temperature for 10 min, and immunostained using antibodies specificfor type II collagen (Abcam), Sox9 (Santa Cruz) and cartilage oligomericmatrix protein (COMP, Santa Cruz), and fluorescently labeled secondaryantibodies (Li-Cor). The total intensity of the staining was measuredusing Oddyssey CLx imaging system (Li-Cor). Vehicle (DMSO) was used ascontrol to determine the basal level of chondrocyte differentiation.Compounds exhibiting 30% or higher increase in staining intensitycompared to vehicle control were selected as active hits. Representativedata are shown in Table 1 [A: >50% increase in staining intensitycompared to vehicle control; B: 30-50% increase in staining intensitycompared to vehicle control].

TABLE 1 Bio- Cmpd Synthetic Characterization Data logical # StructureScheme (NMR and/or LCMS) Activity  1

A LCMS: Found 301.0 [M + H] B  2

A LCMS: Found 301.0 [M + H] LCMS: Found 323.0 [M + Na] B  3

A LCMS: Found 301.0 [M + H] A  4

A LCMS: Found 318.0 [M + H] LCMS: Found 340.0 [M + Na] A  5

A LCMS: Found 318.0 [M + H] LCMS: Found 340.0 [M + Na] B  6

A LCMS: Found 297.0 [M + H] LCMS: Found 615.2 [2M + Na] A  7

A LCMS: Found 297.0 [M + H] LCMS: Found 615.2 [2M + Na] A  8

A LCMS: Found 301.1 [M + H] LCMS: Found 322.9 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 13.19 (S, 1H), 10.72 (S, 1H), 8.05 (D, J = 2.5 Hz, 1H), 7.94(DD, J = 7.7, 1.3 Hz, 1H), 7.84 (DD, J = 8.8, 2.5 Hz, 1H), 7.72-7.55 (M,4H) B  9

A LCMS: Found 335.0 [M + H] LCMS: Found 691.0 [2M + Na] LCMS: Found357.0 [M + Na] A  10

A LCMS: Found 328 [M + H] LCMS: Found 350 [M + Na] LCMS: Found 677 [2M +Na] B  11

A LCMS: Found 344 [M + H] LCMS: Found 366 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 13.19 (S, 1H), 10.19 (S, 1H), 7.93-7.86 (M, 3H), 7.71- 7.58(M, 4H) B  12

A LCMS: Found 344 [M + H] B  13

A LCMS: Found 281.0 [M + H] B  14

A LCMS: Found 350 [M + H] LCMS: Found 372 [M + Na] B  15

B-1 LCMS: Found 303.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 7.10-7.36 (M,6H), 6.56-6.70 (M, 2H), 6.62 (br s, 2H) B  16

B-1 LCMS: Found 298.0 [M + H] A  17

A LCMS: Found 326 [M + H] LCMS: Found 348 [M + Na] B  18

A LCMS: Found 308.0 [M − H] NEG ¹H NMR (400 MHz, DMSO-d₆): 13.12 (S,1H), 10.69 (S, 1H), 8.21 (S, 1H), 7.93-7.85 (M, 2H), 7.71-7.67 (M, 1H),7.63-7.61 (M 3H), 7.46-7.44 (M, 1H) A  19

A LCMS: Found 326 [M + H] LCMS: Found 348 [M + Na] LCMS: Found 673 [2M +Na] ¹H NMR (400 MHz, DMSO-d₆): 13.05 (S, 1H), 10.65 (S, 1H), 7.92-7.87(M, 2H), 7.69-7.45 (M, 5H), 7.09-7.07 (D, J = 8 Hz, 1H) A  21

A LCMS: Found 300 [M + H] LCMS: Found 322 [M + Na] LCMS: Found 622 [2M +Na] A  22

A LCMS: Found 263.1 [M + H] LCMS: Found 571.1 [2M + Na] B  23

C LCMS: Found 314.0 [M + Na] LCMS: Found 292.0 [M + H] A  24

D LCMS: Found 277.2 [M + H] LCMS: Found 299.1 [M + Na] A  25

C LCMS: Found 278.0 [M + H] LCMS: Found 300.0 [M + Na] B  26

B-2 LCMS: Found 289.1 [M + H] B  27

B-2 LCMS: Found 303.1 [M + H] A  28

28 LCMS: Found 255.0 [M + H] ¹H NMR (400 MHz, CDCl₃): 7.50-7.72 (M, 4H),4.85 (br s, 1H), 3.90 (T, 2H, J = 7.2 Hz), 2.53-2.72 (M, 5H), 2.14-2.28(M, 2H) B  29

A LCMS: Found 249 [M + H] LCMS: Found 271 [M + Na] B  30

A LCMS: Found 302 [M + H] LCMS: Found 324 [M + Na] LCMS: Found 625 [2M +Na] B  31

A LCMS: Found 302 [M + H] LCMS: Found 324 [M + Na] LCMS: Found 625 [2M +Na] B  32

A LCMS: Found 314 [M + H] B  33

B-1 LCMS: Found 282.2 [M + H] B  34

A LCMS: Found 307 [M + Na] LCMS: Found 591 [2M + Na] B  35

A LCMS: Found 307 [M + Na] LCMS: Found 591 [2M + Na] ¹H NMR (400 MHz,DMSO-d₆): 13.15 (S, 1H), 10.54 (S, 1H), 8.21-8.19 (D, J = 7.6 Hz, 1H),7.92-7.90 (D, J = 7.6 Hz, 1H), 7.72-7.44 (M, 5H) B  36

A LCMS: Found 284 [M + H] LCMS: Found 307 [M + Na] LCMS: Found 591 [2M +Na] B  37

A LCMS: Found 284 [M + H] LCMS: Found 307 [M + Na] LCMS: Found 591 [2M +Na] ¹H NMR (400 MHz, DMSO-d₆): 13.23 (S, 1H), 10.91 (S, 1H), 7.95-7.88(S, 3H), 7.71-7.69 (M, 1H), 7.65-7.58 (M, 3H) A  38

A LCMS: Found 320.0 [M + H] LCMS: Found 342.0 [M + Na] LCMS: Found 661.0[2M + Na] B  39

D LCMS: Found 277.1 [M + H] LCMS: Found 299.1 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 8.60 (S, 1H), 8.47 (S, 1H), 8.29 (D, 1H), 8.13 (D, 1H),7.78-7.49 (M, 5H), 5.13-5.10 (M, 1H), 3.80 (DD, 1H), 3.41 (DD, 1H) B  40

C LCMS: Found 278.1 [M + H] B  41

C LCMS: Found 287.1 [M + H] LCMS: Found 309.0 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 7.87-7.75 (M, 4H), 7.64-7.45 (M, 4H), 6.09 (M, 1H), 3.86 (DD,1H), 3.62 (DD, 1H) A  42

D LCMS: Found 320.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 8.61 (S, 1H),8.20 (D, J = 8.1 Hz, 2H), 7.92 (D, J = 8.2 Hz, 2H), 7.69-7.59 (M, 3H),7.50 (TD, J = 7.3, 1.3 Hz, 1H), 5.13 (DD, J = 8.0, 4.4 Hz, 1H), 3.80(DD, J = 18.1, 4.4 Hz, 1H), 3.43 (DD, J = 18.1, 8.1 Hz, 1H) B  43

C LCMS: Found 311.0 [M + H] LCMS: Found 333.0 [M + Na] B  44

C LCMS: Found 331.0 [M + H] LCMS: Found 353.0 [M + Na] B  45

H LCMS: Found 330.0 [M + H] LCMS: Found 352.0 [M + Na] B  46

H LCMS: Found 369.0 [M + H] LCMS: Found 391.0 [M + Na] B  47

47 LCMS: Found 300.1 [M + H] B  48

A LCMS: Found 272.0 [M + H] LCMS: Found 294.0 [M + Na] LCMS: Found 565.1[2M + Na] B  49

A LCMS: Found 365.0 [M + Na] LCMS: Found 707.2 [2M + Na] B  50

A LCMS: Found 349.1 [M + Na] B  51

A LCMS: Found 299.1 [M + H] LCMS: Found 321.0 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 13.03 (S, 1H), 10.29 (S, 1H), 7.88 (T, 1H), 7.62 (M, 5 H),7.43 (S, 1H), 7.22 (D, J = 8.4 Hz, 1H), 6.86 (S, 1H), 3.17 (S, 2H) B  52

A LCMS: Found 300.1 [M + H] LCMS: Found 322.0 [M + Na] B  53

E LCMS: Found 322.0 [M + H] LCMS: Found 344.0 [M + Na] B  54

F LCMS: Found 268.1 [M + H] B  55

A LCMS: Found 289.0 [M + H] LCMS: Found 308.0 [M + Na] LCMS: Found 593.0[2M + Na] ¹H NMR (400 MHz, MeOD): 8.71 (D, J = 8 Hz, 1H), 8.13 (M, 1H),8.01 (D, J = 8 Hz, 1H), 7.65 (M, 4H), 7.20 (M, 1H) A  56

G LCMS: Found 330.1 [M + H] A  57

A LCMS: Found 286.2 [M + H] LCMS: Found 308.1 [M + Na] LCMS: Found 593.3[2M + Na] B  58

A LCMS: Found 299.2 [M + H] LCMS: Found 321.2 [M + Na] LCMS: Found 619.1[2M + Na] B  59

A LCMS: Found 313.1 [M + H] LCMS: Found 335.0 [M + Na] LCMS: Found 647.1[2M + Na] B  60

I LCMS: Found 343.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.00 (br s, 1H),10.72 (br s, 1H), 8.03 (S, 1H), 7.82-7.91 (M, 1H), 7.58-7.80 (M, 7H),7.42-7.58 (M, 3H) A  61

I LCMS: Found 343.1 [M + H] A  62

G LCMS: Found 372.2 [M + H] LCMS: Found 394.1 [M + Na] A  63

A LCMS: Found 249 [M + H] LCMS: Found 271 [M + Na] A  64

A LCMS: Found 300.2 [M + H] LCMS: Found 621.2 [2M + Na] ¹H NMR (400 MHz,DMSO-d₆): 12.99 (S, 1H), 10.13 (S, 1H), 7.86 (M, 1H), 7.63 (M, 1H), 7.51(M, 2H), 7.31 (S, 1H), 7.07 (M, 1H), 6.80 (D, J = 8.4 Hz, 1H), 4.23 (M,4H) B  65

A LCMS: Found 286.2 [M + H] LCMS: Found 593.2 [2M + Na] A  66

A LCMS: Found 257.0 [M + H] B  67

A LCMS: Found 257.0 [M + H] A  68

A LCMS: Found 272.0 [M + H] LCMS: Found 294.0 [M + Na] LCMS: Found 565.1[2M + Na] ¹H NMR (400 MHz, DMSO-d₆): 9.37 (S, 1H), 7.98 (D, J = 7.6 Hz,1H), 7.85 (D, J = 7.6 Hz, 1H), 7.65 (M, 1H), 7.58 (M, 2H), 7.15 (M, 1H),7.07 (M, 1H), 6.98 (M, 1H) A  69

A LCMS: Found 392.1 [M + H] LCMS: Found 414.1 [M + Na] B  70

A LCMS: Found 267.1 [M + H] A  71

A LCMS: Found 271.0 [M + H] A  72

A LCMS: Found 349.0 [M + H] LCMS: Found 371.0 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 10.38 (S, 1H), 7.89 (T, 1H), 7.23 (S, 1H), 7.66 (M, 1H), 7.58(M, 4H), 7.07 (D, J = 7.6 Hz, 1H), 4.15 (D, J = 6 Hz, 2H), 2.89 (S, 3H)A  73

A LCMS: Found 363.0 [M + H] LCMS: Found 385.0 [M + Na] LCMS: Found 747.0[2M + Na] ¹H NMR (400 MHz, DMSO-d₆): 13.02 (S, 1H), 10.41 (S, 1H), 7.87(D, J = 7.2 Hz, 1H), 7.65 (M, 3H), 7.35 (T, 1H), 7.04 (D, J = 7.6 Hz,1H), 4.21 (S, 1H), 2.96 (S, 1H), 2.67 (S, 1H) A  74

A LCMS: Found 308.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.53 (S, 1H),7.88 (D, J = 8.4 Hz, 3H), 7.56 (D, J = 8.8 Hz, 2H), 7.65 (M, 1H), 7.59(M, 2H), 7.10 (S, 1H) B  75

F LCMS: Found 295.1 [M + H] LCMS: Found 317.1 [M + Na] ¹H NMR (400 MHz,CDCl₃): ) 9.47 (br s, 1H), 7.86 (D, 1H), 7.79 (D, 2H), 7.57-7.66 (M,3H), 7.48-7.54 (M, 1H), 7.31 (D, 1H), 4.74 (br s, 2H), 3.25 (S, 3H) B 76

H LCMS: Found 330.1 [M + H] B  77

H LCMS: Found 378.1 [M + H] A  78

H LCMS: Found 330.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.70 (S, 1H),7.90 (D, 2H), 7.82 (D, 2H), 7.64-7.49 (M, 4H), 3.26 (S, 3H), 3.00 (S,3H) B  79

H LCMS: Found 360.1 [M + H] ¹H NMR (400 MHz, CDCl₃) 10.85 (S, 1H), 9.97(S, 1H), 7.94 (D, 2H), 7.84 (D, 2H), 7.59-7.63 (M, 2H), 7.30-7.32 (M,1H), 3.61-3.64 (M, 2H), 3.44-3.47 (M, 2H), 3.06 (S, 3H) B  80

A LCMS: Found 233.1 [M + H] LCMS: Found 255.1 [M + Na] LCMS: Found 487.0[2M + Na] B  81

A LCMS: Found 286.0 [M + H] LCMS: Found 308.0 [M + Na] B  82

A LCMS: Found 246.2 [M + H] LCMS: Found 513.2 [2M + Na] A  83

A LCMS: Found 340.0 [M + H] LCMS: Found 362.0 [M + Na] LCMS: Found 701.1[2M + Na] A  84

A LCMS: Found 300.2 [M + H] LCMS: Found 322.1 [M + Na] ¹H NMR (400 MHz,DMSO-d₆): 10.24 (S, 1H), 7.84 (D, J = 6.8 Hz, 1H), 7.56 (M, 4H), 7.15(D, J = 8.8 Hz, 1H), 4.61 (T, 1H), 3.47 (M, 1H), 2.75 (M, 1H), 1.14 (D,J = 6.8 Hz, 3H) A  85

A LCMS: Found 274.2 [M + H] LCMS: Found 296.1 [M + Na] B  86

A LCMS: Found 322.1 [M + H] LCMS: Found 344.0 [M + Na] B  87

A LCMS: Found 302.0 [M + H] LCMS: Found 625.1 [2M + Na] B  88

A LCMS: Found 297.1 [M + H] LCMS: Found 316.0 [M + Na] ¹H NMR (400 MHz,CD₃OD): 8.06-8.04 (D, 1H), 7.75- 7.65 (M, 2H), 7.61-7.53 (M, 3H),7.24-7.24 (D, 2H), 3.95 (S, 3H) —  89

A LCMS: Found 461.0 [M + Na] ¹H NMR (400 MHz, CD₃OD): 8.05 (D, 1H),7.69-7.57 (M, 5H), 7.46-7.35 (M, 6H), 7.20 (D, 1H), 4.45 (S, 2H), 4.16(S, 2H), 2.69 (S, 3H). —  90

A LCMS: Found 377.0 [M + H], LCMS: Found 399.0 [M + Na] ¹H NMR (400 MHz,CD₃OD): 8.05 (D, 1H), 7.72-7.57 (M, 5H), 7.37 (T, 1H), 7.18 (D, 1H),4.39 (S, 2H), 3.15 (Q, 2H), 2.81 (S, 3H), 1.38 (T, 3H). —  91

A LCMS: Found 335.1 [M + H] —  92

A LCMS: Found 318.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.05 (br s, 2H),9.04- 8.98 (M, 1H), 7.92-7.88 (D, 2H), 7.58-7.45 (M, 3H), 7.37-7.33 (M,1H), 4.50 (D, 2H) —  93

A LCMS: Found 318.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.20 (br s, 2H),9.03 (S, 1H), 7.90 (D, 2H), 7.74 (D, 1H), 7.55-7.50 (M, 4H), 4.52 (D,2H) B  94

A LCMS: Found 318.1 [M + H] B  95

A LCMS: Found 318.1 [M + H] —  96

A LCMS: Found 334.0 [M + H] B  97

A LCMS: Found 334.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 9.74 (br s, 1H),9.39 (br s, 1H), 7.90 (D, 2H), 7.59-7.56 (M, 3H), 7.51-7.47 (M, 2H),4.50 (D, 2H) —  98

A LCMS: Found 377.0 [M + H], LCMS: Found 399.0 [M + Na] ¹H NMR (400 MHz,CD₃OD): 8.05 (D, 1H), 7.76-7.57 (M, 5H), 7.37 (T, 1H), 7.20 (D, 1H),4.43 (S, 2H), 3.32- 3.27 (M, 2H), 2.96 (S, 3H), 1.15 (T, 3H). —  99

A LCMS: Found 334.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.10 (br s, 2H),8.93- 8.90 (M, 1H), 7.90 (D, 2H), 7.74 (D, 1H), 7.56-7.51 (M, 3H), 4.51(D, 2H) B 100

A LCMS: Found 334.0 [M + H] B 101

A LCMS: Found 334.1 [M + H] — 102

A LCMS: Found 330.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.96 (br s, 2H),7.90 (D, 2H), 7.51-7.47 (M, 3H), 7.19 (D, 1H), 7.10 (DD, 1H), 4.49 (D,2H), 3.82 (S, 3H) — 103

A LCMS: Found 330.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.90 (br s, 2H),8.65 (T, 1H), 7.91 (D, 2H), 7.54 (D, 2H), 7.45 (D, 2H), 7.32 (DD, 1H),4.48 (D, 1H), 3.83 (S, 3H) A 104

A LCMS: Found 330.0 [M + H] A 105

A LCMS: Found 302.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.98 (br s, 1H),10.19 (S, 1H), 7.86 (D, 1H), 7.67-7.52 (M, 5H), 6.91 (D, 2H), 4.87 (brs, 1H), 3.96 (T, 2H), 3.71 (Q, 2H) B 106

A LCMS: Found 330.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.80 (br s, 2H),7.90 (D, 2H), 7.81 (D, 1H), 7.52 (D, 2H), 7.05 (DD, 1H), 6.95 (D, 1H),4.49 (D, 2H), 3.85 (S, 3H) B 107

A LCMS: Found 349.0 [M + H], LCMS: Found 371.0 [M + Na] ¹H NMR (400 MHz,CD₃OD): 8.06 (D, 1H), 7.83 (S, 1H), 7.69-7.56 (M, 4H), 7.39 (T, 1H),7.23 (D, 1H), 3.32 (S, 3H), 2.95 (S, 3H). B 108

A LCMS: Found 334.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.18 (br s, 2H),9.01 (S, 1H), 7.92 (D, 1H), 7.88 (DD, 1H), 7.80 (DD, 1H), 7.71 (D, 1H),7.63-7.53 (M, 3H), 4.53 (D, 2H) — 109

A LCMS: Found 327.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.98 (br s, 1H),8.81 (S, 1H), 7.76 (D, 2H), 7.58-7.44 (M, 3H), 7.28 (D, 2H), 7.15 (D,2H), 4.40 (D, 2H), 2.77 (Q, 2H), 2.34 (Q, 2H) — 110

G LCMS: Found 365.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.50 (S, 1H), 8.76(D, 1H), 7.82-7.70 (M, 4H), 7.54-7.53 (M, 1H), 7.34-7.30 (m, 2H),3.71-3.69 (m, 4H), 3.05-3.03 (m, 4H). B 111

G LCMS: Found 377.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.38 (S, 1H), 8.74(D, 1H), 7.94-8.07 (M, 2H), 7.80 (D, 1H), 7.68 (D, 1H), 7.25-7.31 (M,1H), 6.95-7.14 (M, 2H), 3.91 (S, 3H), 3.62-3.72 (M, 4H), 2.96-3.11 (M,4H). — 112

G LCMS: Found 415.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.62 (S, 1H), 8.78(D, 1H), 8.14 (D, 2H), 7.84-7.82 (M, 3H), 7.51-7.46 (M, 1H), 7.36-7.32(M, 1H), 3.72-3.69 (M, 4H), 3.05-3.03 (M, 4H). — 113

G LCMS: Found 425.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.68 (S, 1H), 8.78(D, 1H), 8.22 (D, 2H), 8.14 (D, 2H), 7.81 (D, 1H), 7.76- 7.68 (M, 1H),7.37-7.33 (M, 1H), 3.73-3.70 (M, 4H), 3.05-3.03 (M, 4H). A 114

L LCMS: Found 316.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.76 (S, 1H),9.98 (S, 1H), 8.21 (S, 1H), 7.98 (T, 1H), 7.83 (D, 1H), 7.62-7.57 (M,4H), 7.32 (T, 1H), 3.12 (S, 3H) — 115

L LCMS: Found 333.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.70 (br s, 1H),10.18 (br s, 1H), 8.33 (S, 1H), 7.99 (D, 1H), 7.89 (D, 1H), 7.76 (D,1H), 7.58-7.52 (M, 3H), 7.30 (T, 1H), 3.13 (S, 3H), 2.60 (S, 3H) — 116

L LCMS: Found 346.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.60 (S, 1H),10.16 (S, 1H), 8.07 (S, 1H), 7.90 (DD, 2H), 7.59-7.57 (M, 2H), 7.31-7.29(M, 2H), 3.92 (S, 3H), 3.12 (S, 3H) — 117

L LCMS: Found 349.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.44 (S, 1H),10.29 (S, 1H), 7.88 (D, 1H), 7.64-7.55 (M, 4H), 7.31-7.22 (M, 3H), 3.52(Q, 2H), 3.25 (S, 3H), 3.13 (S, 3H), 2.79 (Q, 2H) A 118

G LCMS: Found 365.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.40 (D, 1H), 8.67(D, 1H), 8.14-8.10 (M, 2H), 7.87 (D, 1H), 7.72-7.68 (M, 1H), 7.61-7.55(M, 1H), 7.36-7.30 (M, 4H), 3.71-3.68 (M, 4H), 3.10-3.07 (M, 4H). B 119

L LCMS: Found 349.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.31 (br s, 2H),7.90 (D, 1H), 7.62 (D, 2H), 7.53 (S, 2H), 7.20-7.18 (M, 3H), 4.49-4.46(M, 1H), 3.43-3.39 (M, 2H), 3.08 (S, 3H), 2.65-2.55 (M, 2H), 1.74-1.67(M, 2H) — 120

L LCMS: Found 349.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.91 (br s, 1H),11.13 (br s, 1H), 9.51 (T, 1H), 7.94-7.91 (M, 3H), 7.57 (S, 2H), 7.46(D, 2H), 7.24-7.21 (M, 1H), 4.56 (D, 2H), 3.12 (S, 3H) B 121

J LCMS: Found 372.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.37 (S, 1H),8.37 (S, 1H), 8.26 (M, 1H), 8.14-8.12 (M, 2H), 7.86-7.79 (M, 3H), 7.52(M, 1H), 3.56-3.54 (T, 4H), 2.83-2.86 (T, 4H) — 122

J LCMS: Found 389.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.42 (S, 1H),8.51 (S, 1H), 8.30 (D, 1H), 8.23-8.19 (M, 2H), 7.87-7.74 (M, 3H), 7.50(T, 1H), 3.57-3.55 (M, 4H), 2.92-2.89 (M, 4H), 2.67 (S, 3H) A 123

J LCMS: Found 365.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.27 (S, 1H),8.30 (D, 1H), 8.05-8.01 (M, 2H), 7.84-7.80 (M, 2H), 7.47- 7.41 (M, 3H),3.62-3.55 (M, 4H), 2.95-2.88 (M, 4H) A 124

G LCMS: Found 383.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.36 (D, 1H), 8.64(D, 1H), 8.20-8.14 (M, 1H), 7.85 (D, 1H), 7.69 (T, 1H), 7.35-7.29 (M,2H), 7.10-6.95 (M, 2H), 3.71-3.69 (M, 4H), 3.09-3.06 (M, 4H). — 125

G LCMS: Found 353.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.40 (S, 1H), 8.66(D, 1H), 8.07-8.04 (M, 2H), 7.85 (D, 1H), 7.60 (T, 1H), 7.32-7.20 (M,3H), 3.73-3.71 (M, 2H), 3.25-3.23 (M, 2H), 2.86 (S, 3H). B 126

G LCMS: Found 364.2 [M + H] ¹H NMR (400 MHz, CDCl₃ + CD₃OD): 8.60 (D,1H), 7.97-7.94 (M, 2H), 7.80 (D, 1H), 7.70 (T, 1H), 7.32- 7.16 (M, 3H),3.37-3.33 (M, 4H), 3.18-3.15 (M, 4H). — 127

G LCMS: Found 378.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.17 (S, 1H), 8.73(D, 1H), 8.03-8.00 (M, 2H), 7.80 (D, 1H), 7.74 (T, 1H), 7.35-7.22 (M,3H), 3.81 (br s, 2H), 3.56 (br s, 2H), 3.29 (br s, 2H), 2.90 (br s, 2H),2.81 (S, 3H). — 128

G LCMS: Found 379.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.28 (S, 1H), 8.64(D, 1H), 8.06-8.03 (M, 2H), 7.89 (D, 1H), 7.65 (T, 1H), 7.30-7.21 (M,3H), 3.87-3.85 (M, 1H), 3.75 (D, 1H), 3.55-3.26 (M, 5H), 1.19 (D, 3H). A129

G LCMS: Found 399.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.55 (S, 1H), 8.76(D, 1H), 8.05-8.02 (M, 2H), 7.90 (D, 1H), 7.69 (T, 1H), 7.33-7.17 (M,8H), 4.19 (S, 2H), 2.63 (S, 3H). — 130

A LCMS: Found 325.1 [M + H] — 131

A LCMS: Found 325.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.15 (br s, 1H),10.58 (S, 1H), 7.92 (D, 1H), 7.72-7.53 (M, 6H), 4.54 (T, 1H), 4.42-4.39(M, 2H), 2.68-2.65 (M, 2H), 1.76-1.69 (M, 2H) — 132

G LCMS: Found 385.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 9.84 (S, 1H), 8.63(D, 1H), 7.89 (D, 1H), 7.67-7.59 (M, 3H), 7.30-7.28 (M, 1H), 7.11-7.05(M, 6H), 6.95-6.93 (M, 1H), 3.19 (S, 3H). — 133

G LCMS: Found 423.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.54 (S, 1H), 8.79(D, 1H), 8.10 (D, 2H), 7.83-7.66 (M, 6H), 7.54-7.42 (M, 3H), 7.33-7.29(M, 1H), 3.71-3.69 (M, 4H), 3.07-3.05 (M, 4H). B 134

A LCMS: Found 318.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.10 (br s, 1H),10.49 (S, 1H), 7.89 (D, 1H), 7.63-7.53 (M, 4H), 7.31 (D, 2H), 7.23 (T,1H), 4.51 (T, 1H), 3.45-3.42 (M, 2H), 2.62- 2.58 (M, 2H), 1.71-1.65 (M,2H) — 135

A LCMS: Found 334.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.09 (br s, 1H),10.44 (S, 1H), 7.90-7.84 (M, 2H), 7.67-7.49 (M, 4H), 7.28 (D, 2H), 4.53(T, 1H), 3.46-3.42 (M, 2H), 2.70-2.66 (M, 2H), 1.73-1.66 (M, 2H) — 136

A LCMS: Found 314.1 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.17 (S, 1H),7.86-7.84 (D, 1H), 7.63-7.62 (D, 1H), 7.55-7.47 (M, 3H), 7.40- 7.35 (D,1H), 7.06-7.04 (D, 1H), 4.49-4.47 (T, 1H), 3.45-3.41 (M, 2H), 2.57-2.53(M, 2H), 2.24 (S, 3H), 1.67-1.60 (M, 2H) — 137

A LCMS: Found 343.0 [M + H] — 138

A LCMS: Found 344.1 [M + H] — 139

G LCMS: Found 383.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.50 (S, 1H), 8.73(D, 1H), 7.92 (T, 1H), 7.82-7.70 (M, 3H), 7.40-7.29 (M, 2H), 3.72-3.70(M, 4H), 3.05-3.02 (M, 4H). — 140

A LCMS: Found 311.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.10 (br s, 1H),10.51 (S, 1H), 8.02 (S, 1H), 7.90-7.82 (M, 2H), 7.67-7.55 (M, 3H), 7.26(D, 1H), 4.18 (Q, 2H), 1.37 (T, 3H) — 141

G LCMS: Found 412.9 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.33 (D, 1H),8.11-8.08 (M, 2H), 7.98 (D, 1H), 7.79 (T, 1H), 7.49 (T, 1H), 7.36- 7.31(M, 2H), 3.68-3.66 (M, 4H), 3.28-3.16 (M, 4H). B 142

A LCMS: Found 299.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.99 (br s, 1H),10.27 (S, 1H), 9.89 (S, 1H), 7.87 (D, 1H), 7.67-7.50 (M, 7H), 2.03 (S,3H) B 143

A LCMS: Found 316.1 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.03-8.01 (T, 1H),7.66- 7.63 (T, 1H), 7.58-7.52 (M, 4H), 6.94-6.92 (M, 2H), 4.12-4.10 (M,2H), 3.75-3.73 (M, 2H), 3.42 (S, 3H) — 144

G LCMS: Found 429.0 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.40 (D, 1H), 7.99(D, 1H), 7.74 (T, 1H), 7.65-7.57 (M, 4H), 7.42 (T, 1H), (M, 4H), 3.19(S, 3H). — 145

A LCMS: Found 312.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 11.18 (br s, 1H),7.80 (D, 1H), 7.62-7.50 (M, 5H), 7.22 (T, 1H), 6.91 (D, 1H), 2.75 (S,3H), 2.12-2.09 (M, 2H) B 146

G LCMS: Found 405.0 [M + H], LCMS: Found 427.0 [M + Na] ¹H NMR (400 MHz,CD₃OD): 8.53 (D, 1H), 7.93 (D, 2H), 7.88 (D, 1H), 7.76 (T, 1H), 7.47 (D,2H), 7.42 (D, 1H), 3.68 (T, 2H), 3.64-3.62 (M, 4H), 3.36 (S, 3H),3.01-2.96 (M, 6H). — 147

G LCMS: Found 391.0 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.53 (D, 1H), 8.22(D, 2H), 8.12 (D, 2H), 7.92 (D, 1H), 7.80 (T, 1H), 7.44 (T, 1H),3.65-3.63 (M, 4H), 3.02-3.00 (M, 4H). B 148

A LCMS: 384.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 11.18 (br s, 1H), 7.80(D, 1H), 7.62-7.50 (M, 5H), 7.22 (T, 1H), 6.91 (D, 1H), 2.75 (S, 3H),2.12-2.09 (M, 2H) B 149

A LCMS: Found 325.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.09 (S, 1H),10.48 (S, 1H), 8.01-8.01 (D, 1H), 7.90-7.88 (D, 1H), 7.81- 7.80 (D, 1H),7.67 (S, 1H), 7.59-7.56 (D, 2H), 7.31-7.28 (D, 2H), 4.77-4.72 (M, 1H),1.32-1.31 (D, 6H) — 150

A LCMS: Found 318.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.03 (S, 1H),10.05 (S, 1H), 7.88-7.86 (D, 2H), 7.07-7.65 (M, 2H), 7.57- 5.52 (M, 2H),7.11-7.03 (M, 2H), 4.50 (S, 1H), 3.42- 3.41 (D, 2H), 2.64-2.60 (T, 2H),1.76-1.69 (M, 2H) — 151

A LCMS: Found 334.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.13 (S, 1H),9.93 (S, 1H), 7.88-7.86 (D, 1H), 7.66-7.65 (M, 1H), 7.59-7.54 (M, 3H),7.35 (S, 1H), 7.22-7.20 (D, 1H), 4.50 (S, 1H), 3.43-3.39 (M, 2H),2.64-2.60 (T, 2H), 1.74-1.68 (M, 2H) — 152

G LCMS: Found 405.0 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.36 (D, 1H), 8.05(D, 2H), 7.76 (D, 1H), 7.67 (T, 1H), 7.53 (D, 2H), 7.35 (T, 1H), 3.88(S, 2H), 3.51-3.48 (M, 4H), 2.64-2.62 (M, 4H). — 153

A LCMS: Found 314.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.91 (br s, 2H),8.98 (S, 1H), 7.80-7.75 (M, 2H), 7.58-7.50 (M, 3H), 7.31- 7.28 (M, 2H),4.46-4.04 (M, 2H) — 154

A LCMS: Found 330.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.95 (br s, 1H),12.55 (br s, 1H), 8.93 (S, 1H), 7.78 (D, 1H), 7.62- 7.49 (M, 4H), 7.16(D, 1H), 4.47 (D, 2H), 3.84 (S, 3H) B 155

A LCMS: Found 325.0 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.37 (br s, 1H),8.99 (T, 1H), 8.07 (D, 1H), 7.97 (S, 1H), 7.83-7.80 (M, 2H), 7.62-7.51(M, 3H), 4.54 (D, 2H) A 156

H LCMS: Found 455.1 [M + 2Na − H] ¹H NMR (400 MHz, CDCl₃): 10.36 (S,1H), 7.82-7.75 (M, 3H), 7.51-7.43 (M, 5H), 7.37-7.33 (M, 2H), 7.29- 7.27(M, 2H), 7.16 (T, 1H), 4.38 (T, 2H), 3.81 (S, 3H), 3.02 (T, 2H). A 157

A LCMS: Found 314.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.92 (br s, 2H),8.86 (T, 1H), 7.79-7.73 (M, 3H), 7.60-7.48 (M, 4H), 4.45 (D, 2H), 2.38(S, 3H) — 158

A LCMS: 314.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.97 (br s, 2H), 8.83(D, 1H), 8.02 (D, 1H), 7.91 (D, 1H), 7.79 (D, 1H), 7.61-7.55 (M, 3H),7.44 (D, 1H), 5.18-5.11 (M, 1H), 1.44 (D, 3H) — 159

H LCMS: Found 421.2 [M + 2Na − H] ¹H NMR (400 MHz, CDCl₃): 10.36 (S,1H), 7.96 (S, 1H), 7.79 (D, 1H), 7.67 (D, 1H), 7.56-7.51 (M, 3H),7.29-7.27 (M, 1H), 7.19 (T, 1H), 4.36 (T, 2H), 3.80 (S, 3H), 3.14 (T,2H), 3.01 (T, 2H), 1.91-1.85 (M, 2H), 1.02 (T, 3H). B 160

A LCMS: Found 297.1 [M + H] — 161

A LCMS: Found 368.1 [M + H] ¹H NMR (400 MHz, CD₃OD): 8.08-8.06 (D, 2H),8.01- 7.99 (D, 1H), 7.68-7.64 (M, 3H), 7.56-7.56 (D, 1H), (D, 1H),6.03-5.97 (M, 1H) — 162

H LCMS: Found 421.2 [M + 2Na − H] ¹H NMR (400 MHz, CDCl₃): 10.35 (S,1H), 7.95 (S, 1H), 7.85 (D, 1H), 7.65 (D, 1H), 7.56-7.48 (M, 3H),7.31-7.27 (M, 1H), 7.16 (T, 1H), 4.36 (T, 2H), 3.80 (S, 3H), 3.37-3.32(M, 1H), 3.01 (T, 2H), 1.41 (S, 6H). B 163

H LCMS: Found 469.2 [M + 2Na − H] ¹H NMR (400 MHz, CDCl₃): 10.42 (S,1H), 7.80 (S, 1H), 7.67 (D, 1H), 7.61 (D, 1H), 7.50-7.44 (M, 3H),7.29-7.24 (M, 6H), 7.16 (T, 1H), 4.42 (S, 2H), 4.37 (T, 2H), 3.80 (S,3H), 3.01 (T, 2H). — 164

A LCMS: Found 314.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.70 (br s, 2H),8.83 (T, 1H), 7.76 (D, 1H), 7.59-7.45 (M, 3H), 7.32 (D, 2H), 7.20 (D,2H), 4.41 (D, 2H), 3.55 (S, 2H) A 165

K-1 LCMS: Found 279.0 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.98 (S, 1H),8.80 (S, 1H), 8.46 (D, 1H), 8.03 (D, 1H), 7.61-7.56 (M, 1H), 7.28-7.11(M, 1H), 3.92 (S, 3H) — 166

A LCMS: Found 312.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.99 (br s, 1H),8.84 (T, 1H), 7.76 (D, 1H), 7.59-7.47 (M, 3H), 7.33 (D, 2H), 7.14 (D,2H), 4.41 (D, 2H), 3.74 (S, 2H), 2.12 (S, 3H) B 167

A LCMS: Found 318.1 [M + H] — 168

A LCMS: Found 330.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 9.39 (br s, 2H),7.71 (D, 1H), 7.59-7.47 (M, 6H), 4.43 (D, 2H), 3.55 (S, 2H) — 169

K-1 LCMS: Found 343.0 [M + H] LCMS: Found 365.0 [M + Na] ¹H NMR (400MHz, CDCl₃): 10.48 (S, 1H), 8.56 (D, 1H), 8.04-7.79 (M, 3H), 7.60 (D,1H), 7.53 (T, 1H), 7.45 (T, 1H), 7.02-6.98 (M, 1H), 5.11 (br s, 1H),4.56 (D, 2H), 3.94 (S, 3H), 3.91 (S, 3H) — 170

A LCMS: Found 298.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.03 (br s, 1H),8.94 (T, 1H), 7.92 (D, 2H), 7.78 (D, 2H), 7.61-7.49 (M, 5H), 4.50 (D,2H), 2.58 (S, 3H) — 171

K-1 LCMS: Found 357.0 [M + H] LCMS: Found 379.0 [M + Na] ¹H NMR (400MHz, CDCl₃): 10.50 (S, 1H), 8.56 (D, 1H), 8.05-8.01 (M, 3H), 7.53 (T,1H), 7.44 (D, 1H), 7.00 (T, 1H), 5.10 (br s, 1H), 4.57 (D, 2H), 4.38 (Q,2H), 3.91 (S, 3H), 1.41 (T, 3H) — 172

A LCMS: Found 299.1 [M + H] B 173

A LCMS: Found 328.2 [M + H] — 174

A LCMS: Found 300.1 [M + H] ¹H NMR (400 MHz, CD₃OD): 7.98-7.97 (D, 1H),7.63- 7.51 (M, 5H), 7.39-7.36 (T, 3H), 5.68 (S, 1H) — 175

A LCMS: Found 365.1 [M + Na] ¹H NMR (400 MHz, DMSO-d₆): 13.09 (br s,1H), 12.09 (S, 1H), 8.49 (D, 1H), 8.30 (S, 1H), 7.82 (D, 1H), 7.7- 7.61(M, 4H), 7.36 (D, 1H), 4.52 (T, 1H), 3.44-3.41 (M, 2H), 2.63-2.60 (M,2H), 1.78-1.71 (M, 2H) — 176

A LCMS: Found 344.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.12 (S, 1H),11.42 (S, 1H), 8.52-8.50 (D, 1H), 7.86-7.83 (M, 2H), 7.70- 7.64 (M, 3H),7.62 (D, 1H), 4.49 (S, 1H), 3.41 (M, 2H), 2.65-2.62 (T, 2H), 1.75-1.68(M, 2H) B 177

B-3 LCMS: Found 318.9 [M + H] LCMS: Found 301.0 [M − H ] ¹H NMR (400MHz, DMSO-d₆): 8.07 (D, 2H), 7.84 (D, 2H), 7.83-7.71 (M, 3H), 7.64 (T,1H), 7.42 (br s, 1H), 7.03 (br s, 1H), 6.66 (S, 1H), 2.44 (S, 3H). — 178

A LCMS: Found 330.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.03 (S, 1H),10.26 (S, 1H), 7.88 (D, 1H), 7.64 (D, 1H), 7.59-7.52 (M, 2H), 7.41 (S,1H), 7.17 (D, 1H), 7.06 (D, 1H), 4.43 (T, 1H), 3.75 (S, 3H), 3.43-3.38(M, 2H), 2.51-2.50 (M, 2H), 1.67-1.65 (M, 2H) B 179

A LCMS: Found 341.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.21 (br s, 1H),10.56 (S, 1H), 8.03 (D, 1H), 7.90 (D, 1H), 7.80 (D, 1H), 7.69- 7.55 (M,3H), 7.17 (D, 1H), 4.87 (S, 2H) — 180

A LCMS: Found 318.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.13 (br s, 1H),10.31 (S, 1H), 7.96 (D, 1H), 7.63-7.39 (M, 5H), 7.15 (D, 2H), 4.47 (T,1H), 3.42-3.40 (M, 2H), 2.59-2.53 (M, 2H), 1.73-1.66 (M, 2H) B 181

A LCMS: Found 318.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.25 (br s, 1H),10.46 (S, 1H), 7.64-7.45 (M, 6H), 7.15 (D, 2H), 4.47 (T, 1H), 3.43-3.37(M, 2H), 2.60-2.56 (M, 2H), 1.74-1.66 (M, 2H) B 182

A LCMS: Found 318.1 [M + H] B 183

A LCMS: Found 318.1 [M + H] B 184

A LCMS: Found 334.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.30 (br s, 1H),10.31 (S, 1H), 7.90-7.55 (M, 6H), 7.15 (D, 2H), 4.47 (br s, 1H),3.43-3.38 (M, 2H), 2.60-2.55 (M, 2H), 1.73-1.68 (M, 2H) B 185

A LCMS: Found 334.1 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.46 (S, 1H),7.727.68 (M, 2H), 7.61-7.54 (M, 3H), 7.16 (D, 2H), 4.47 (S, 1H),3.43-3.39 (M, 2H), 2.60-2.50 (M, 2H), 1.74-1.66 (M, 2H) B 186

A LCMS: Found 334.1 [M + H] B 187

A LCMS: Found 334.1 [M + H] B 188

A LCMS: Found 314.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 12.85 (br s, 1H),10.19 (S, 1H), 7.79-7.56 (M, 3H), 7.44-7.33 (M, 2H), 7.13 (D, 2H), 4.47(T, 1H), 3.42-3.39 (M, 2H), 2.59-2.51 (M, 2H), 1.73-1.66 (M, 2H) — 189

A LCMS: Found 314.2 [M + H] ¹H NMR (400 MHz, MeOD): 7.59-7.53 (M, 3H),7.48- 7.41 (M, 2H), 7.18-7.14 (M, 2H), 3.60-3.57 (T, 2H), 2.72-2.67 (M,2H), 2.47 (S, 3H), 1.88-1.81 (M, 2H) A 190

A LCMS: Found 314.2 [M + H] A 191

A LCMS: Found 314.2 [M + H] — 192

A LCMS: Found 342.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 13.04 (br s, 1H),10.28 (S, 1H), 7.86 (D, 1H), 7.65-7.53 (M, 5H), 7.19 (D, 2H), 3.86-3.77(M, 4H), 2.81 (S, 2H), 1.19 (S, 3H) — 193

K-1 LCMS: Found 313.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆):10.63 (S, 1H),8.53 (D, 1H), 8.03 (M, 2H), 7.75 (D, 1H), 7.68 (D, 1H), 7.53 (T, 1H),7.42 (T, 1H), 7.04 (M, 1H), 3.90 (S, 3H), 2.30 (S, 3H) B 194

K-1 LCMS: Found 339.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.70 (S, 1H),8.50 (D, 1H), 8.00 (T, 2H), 7.65 (D, 1H), 7.55 (M, 2H), 7.26 (M, 1H),6.67 (S, 1H), 3.88 (S, 3H) B 195

K-1 LCMS: Found 339.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.65 (S, 1H),8.55 (D, 1H), 8.02 (D, 1H), 7.81 (S, 1H), 7.62 (D, 1H), 7.55 (T, 1H),7.45 (T, 1H), 7.26 (D, 1H), 7.05 (T, 1H), 6.95 (S, 1H), 3.91 (S, 3H) B196

K-2 LCMS: Found 307.1 [M − H₂O + H] ¹H NMR (400 MHz, DMSO-d₆): 11.63 (S,1H), 7.95 (D, 1H), 7.82 (M, 1H), 7.81 (S, 1H), 7.73 (M, 2H), 7.68 (M,1H), 7.24 (M, 2H) B 197

K-1 LCMS: Found 285.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 9.96 (S, 1H),9.01 (S, H), 8.29 (D, 1H), 7.92 (DD, 1H), 7.55 (T, 1H), 7.46 (DD, 1H),7.22-7.16 (M, 2H), 7.07-7.04 (M, 2H), 3.87 (S, 3H), 2.25 (S, 3H) B 198

K-1 LCMS: Found 285.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.47 (S, 1H),8.55 (D, 1H), 7.99 (D, 1H), 7.51 (T, 1H), 7.30 (D, 2H), 7.16 (D, 2H),7.0 (T, 1H), 6.68 (S, 1H), 3.87 (S, 3H), 2.33 (S, 3H) B 199

K-2 LCMS: Found 253.2 [M − H₂O + H] ¹H NMR (400 MHz, DMSO-d₆): 11.60 (S,1H), 7.96 (D, 1H), 7.72 (T, 1H), 7.35 (M, 2H), 7.30 (M, 1H), 7.22 (M,3H), 3.32 (S, 3H) B 200

K-1 LCMS: Found 271.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.50 (S, 1H),8.55 (D, 1H, J = 6 Hz), 7.97 (D, 1H, J = 7.8 Hz), 7.52 (M, 1H), 7.44 (M,1H), 7.34 (M, 2H), 7.11 (M, 1H), 7.00 (M, 1H), 6.84 (S, 1H), 3.88 (S,3H) B 201

K-1 LCMS: Found 321.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.64 (S, 1H),8.60 (DD, 1H), 8.08-7.98 (M, 2H), 7.83-7.74 (M, 3H), 7.55 (DD, 1H),7.49-7.34 (M, 3H), 7.06-6.97 (M, 1H), 6.95 (S, 1H), 3.89 (S, 3H) B 202

K-1 LCMS: Found 296.2 [M + H] ¹H NMR (400 MHz, CDCl₃): 10.70 (S, 1H),8.52 (DD, 1H), 8.02 (DD, 1H), 7.89 (T, 1H), 7.64 (DD, 1H), 7.56 (DD,1H), 7.45-7.33 (M, 2H), 7.05 (DD, 1H), 6.92 (S, 1H), 3.93 (S, 3H) A 203

K-2 LCMS: Found 238.07 [M − H₂O + H] ¹H NMR (400 MHz, DMSO-d₆): 11.56(S, 2H), 7.94 (D, 1H, J = 8 Hz), 7.70 (T, 1H, J = 6 Hz), 7.48 (M, 2H),7.42 (M, 1H), 7.32 (M, 2H), 7.22 (M, 2H) B 204

K-2 LCMS: Found 280.08 [M − H₂O + H] ¹H NMR (400 MHz, DMSO-d₆): 11.60(S, 2H), 8.03 (D, 2H, J = 6 Hz), 7.95 (M, 2H), 7.72 (T, 2H, J = 6 Hz),7.25 (D, 2H, J = 6.4 Hz), 3.32 (S, 3H) B 205

K-2 LCMS: Found 281.2 [M − H₂O + H] ¹H NMR (400 MHz, DMSO-d₆): 11.55 (S,1H), 8.05 (D, 1H), 7.90 (D, 1H), 7.70 (M, 2H), 7.61 (M, 1H), 7.42 (D,1H), 7.23 (M, 2H), 2.46 (S, 3H) B 206

K-1 LCMS: Found 313.2 [M + H] ¹H NMR (400 MHz, DMSO-d₆): 10.67 (S, 2H),8.52 (D, 1H, J = 7.8 Hz), 8.00 (D, 1H), 7.94 (D, 2H, J = 8 Hz), 7.55 (M,3H), 7.03 (T, 1H, J = 6 Hz), 3.88 (S, 3H), 2.58 (S, 3H) B

Example 2 Cell Viability Assay

Human MSCs, chondrocytes, osteoblasts and synoviocytes are plated into384-well plates at 10,000 cells per well. Compounds are added at a finalconcentration of 100 μM. The cells are cultured for 48 h. Cell viabilityis analyzed by Cell Titer-Glo (Promega) assay using EnVision platereader (PerkinElmer). Apoptosis activity is analyzed by Caspase 3/7-Glo(Promega) assay using EnVision plate reader (PerkinElmer).

Example 3 PK Study Via Intra-Articular Injection in Rats

A 30 μl-compound solution (100 μM in PBS containing 0.1% DMSO) isinjected into the articular space of the right knee of each rat. Theanimals are bled at 1, 3, 4, 6, 7, 8, 9, and 10 hours post-injection.The animals are terminated at 2 or 12 hours post-dose. Plasma and jointlavage of the injected knees are collected. The quantities of theinjected compounds are analyzed using LCMS.

Example 4 Rat Medial Meniscal Tear (MMT) Osteoarthritis (OA) Model

The medial meniscus of the right knee of each animal is surgically tornto induce OA. Dosing of the compound solutions (30 μl of 100 μM in PBScontaining 0.1% DMSO) is begun 7 days post-surgery at one dose per weekfor three weeks. Body weights and gait deficits are monitored weeklyright before dosing. Animals are terminated at day 28 post-surgery. Thejoints of the operated knees are processed and histochemically stainedfor cartilage, and the cartilage is evaluated.

Following 4-6 days in 5% formic acid decalcifier, the operated jointsare cut into two approximately equal halves in the frontal plane andembedded in paraffin. Three sections are cut from each operated rightknee (g1-8) at approximately 200 μm steps and stained with toluidineblue. Left knees of group 1 and right knees from group 9 have a singlesection prepared and stained with toluidine blue.

All three sections of each operated knee are analyzed microscopically.The worst-case scenario for the two halves on each slide is determinedfor general cartilage degeneration, proteoglycan loss, collagen damage,and osteophyte formation. The values for each parameter are thenaveraged across the three sections to determine overall subjectivescores.

In addition, for some parameters (noted below), regional differencesacross the tibial plateau are taken into consideration by dividing eachsection into three zones (1-outside, 2-middle, 3-inside). In thesurgical OA model, the outside (z1) and middle (z2) thirds are mostseverely affected, and milder changes are present on the inside third(z3). When zones are scored individually, scores are assigned based onpercent area of the zone affected. Zone areas are delineated using anocular micrometer.

The following parameters are measured and/or scored:

General cartilage degeneration includes the important parameters ofchondrocyte death/loss, proteoglycan loss, and collagen loss orfibrillation. Cartilage degeneration in the tibia is scored none tosevere (numerical values 0-5) for each zone using the followingcriteria:

-   -   0=no degeneration    -   1=minimal degeneration, within the zone 5-10% of the matrix        appears non viable as a result of significant chondrocyte loss        (greater than 50% of normal cell density). PG loss is usually        present in these areas of cell loss and collagen matrix loss may        be present.    -   2=mild degeneration, within the zone 11-25% of the matrix        appears non viable as a result of significant chondrocyte loss        (greater than 50% of normal cell density). PG loss is usually        present in these areas of cell loss and collagen matrix loss may        be present.    -   3=moderate degeneration, within the zone 26-50% of the matrix        appears non viable as a result of significant chondrocyte loss        (greater than 50% of normal cell density). PG loss is usually        present in these areas of cell loss and collagen matrix loss may        be present.    -   4=marked degeneration, within the zone 51-75% of the matrix        appears non viable as a result of significant chondrocyte loss        (greater than 50% of normal cell density). PG loss is usually        present in these areas of cell loss and collagen matrix loss may        be present.    -   5=severe degeneration, within the zone 76-100% of the matrix        appears non viable as a result of significant chondrocyte loss        (greater than 50% of normal cell density). PG loss is usually        present in these areas of cell loss and collagen matrix loss may        be present.        In some cases, image analysis may be used to determine the exact        % of matrix viability and/or loss in each zone or in selected        zones so that absolute % rather than scores (0-5) can be        compared. A 3-zone sum for cartilage degeneration is calculated        in addition to expressing the data for each zone.

The same process is applied to evaluation of the femoral cartilage withthe exception that lesions are not analyzed based on zones since thelesions are not generally distributed over the surface in a zonalpattern. The total width of the load-bearing surface (approximately 2000μm for the femur) is determined and the above criteria is applied to themost severely affected 1/3, 2/3 or 3/3. For example, if 1/3 of the totalarea (lesion may be in the center of the plateau covering about 667 μm)has minimal degeneration (5-10% of total area has loss of chondrocytesand/or matrix), a score of 11 s assigned. If that minimal degenerationextends over the entire surface (3/3) then the score is 3. If the entirefemoral cartilage is absent as a result of severe diffuse degeneration,then the score is 15.

In addition to this overall cartilage degeneration score, collagenmatrix damage is scored separately in order to identify more specificeffects of agents. Collagen damage across the medial tibial plateau(most severely affected section of the two halves) is quantified bymeasuring the total width of the following:

-   -   Any damage (fibrillation ranging from superficial to full        thickness loss).    -   Severe damage (total or near total loss of collagen to        tidemark, >90% thickness)    -   Marked damage (extends through 61-90% of the cartilage        thickness)    -   Moderate damage (extends thru 31-60% of the cartilage thickness)    -   Mild damage (extends through 11-30% of the cartilage thickness)    -   Minimal damage (very superficial, affecting upper 10% only)

In addition to the above subjective general cartilage scoring, twocartilage degeneration width measurements are taken:

-   -   Total Tibial Cartilage Degeneration Width (μm) is a micrometer        measurement of total extent of tibial plateau affected by any        type of degeneration (cell loss, proteoglycan loss or collagen        damage). This measurement extends from the origination of the        osteophyte with adjacent cartilage degeneration (outside 1/3)        across the surface to the point where tangential layer and        underlying cartilage appear histologically normal.    -   Substantial Cartilage Degeneration Width (μm) reflects areas        oftibial cartilage degeneration in which both chondrocyte and        proteoglycan loss extend through greater than 50% of the        cartilage thickness. In general, the collagen damage is mild        (25% depth) or greater for this parameter but chondrocyte and        proteoglycan loss extend to at least 50% or greater of the        cartilage depth.

A micrometer depth of any type of lesion (both chondrocyte andproteoglycan loss, but may have good retention of collagenous matrix andno fibrillation), expressed as a ratio of depth of changed area vs.depth to tidemark, is taken in the area of greatest lesion severity ineach of the three zones across the tibial surface at the midpoint of thezone. This measurement is the most critical analysis of any type ofmicroscopic change present. The denominator can serve as an averagemeasure of cartilage thickness in each of the three zones for comparisonof anabolics when measures are taken at the midpoint of the zone.

Scoring of the osteophytes and categorization into small, medium andlarge is done with an ocular micrometer. Marginal zone proliferativechanges have to be >200 μm in order to be measured and designated asosteophytes. Scores are assigned to the largest osteophyte in eachsection (typically found in the tibia) according to the followingcriteria:

-   -   1=small up to 299 μm    -   2=moderate 300-399 μm    -   3=large 400-499 μm    -   4=very large 500-599    -   5=very large ≧600        The actual osteophyte measurement (tidemark to furthest distance        point extending toward synovium) is also recorded.

The femoral cartilage degeneration score and the three-zone sum of thetibial cartilage degeneration scores (mean of three levels) are summedto create a total cartilage degeneration score. The mean osteophytescore for each joint is added to this value to produce a total jointscore.

Image Analysis

In order to quantify and compare the cartilage matrix preservation,cartilage area measurements are taken from the most severely affectedsection of each animal. Photomicrographs are taken with a CoolSNAP-Promicroscope camera and loaded into ImagePro Plus software. The followingmeasurements are taken from tracings of these photomicrographs, four perpage, which are included in the report:

-   -   Total area from the tidemark to the surface (or projected        surface in degenerated areas) over 9 cm (photomicrograph) of the        tibial plateau, measured from the inner edge of the osteophyte    -   Area of non-viable matrix (cartilage with less than 50%        chondrocytes, proteoglycan, and intact collagen) and no matrix        within the total area    -   Area of no matrix within the total area        The area of non-viable matrix is subtracted from the total area        to get the area of viable matrix, and the area of no matrix is        subtracted from the total area to get the area of any matrix        (collagen matrix with or without chondrocytes and proteoglycan).        These two values are then compared back to the total area to        derive the percent viable matrix area and the percent any matrix        area, which are compared between groups. Five left knees from        the vehicle group are included in this process as normal        controls. This process may be used to analyze the entire surface        or selected zones depending on lesion severity and apparent        treatment effects.

Synovial reaction, if abnormal, is described (should be mainly fibrosis)and characterized with respect to inflammation type and degree but isnot included in the OA score.

Damage to the calcified cartilage layer and subchondral bone (worst casescenario for all sections) is scored using the following criteria:

-   -   0=No changes    -   1=Increased basophilia at tidemark, no fragmentation of        tidemark, no marrow changes or if present minimal and focal    -   2=Increased basophilia at tidemark, minimal to mild focal        fragmentation of calcified cartilage of tidemark, mesenchymal        change in marrow involves 1/4 of total area but generally is        restricted to subchondral region under lesion    -   3=Increased basophilia at tidemark, mild to marked focal or        multifocal fragmentation of calcified cartilage (multifocal),        mesenchymal change in marrow is up to 3/4 of total area, areas        of marrow chondrogenesis may be evident but no major collapse of        articular cartilage into epiphyseal bone (definite depression in        surface)    -   4=Increased basophilia at tidemark, marked to severe        fragmentation of calcified cartilage, marrow mesenchymal change        involves up to 3/4 of area and articular cartilage has collapsed        into the epiphysis to a depth of 250 μm or less from tidemark        (see definite depression in surface cartilage)    -   5=Increased basophilia at tidemark, marked to severe        fragmentation of calcified cartilage, marrow mesenchymal change        involves up to 3/4 of area and articular cartilage has collapsed        into the epiphysis to a depth of greater than 250 μm from        tidemark        In addition, measurements are made of the thickness of the        medial synovial/collateral ligament repair in a non-tangential        area of the section.

Growth plate thickness is measured in all knees on medial and lateralsides (2 measures/joint) at the approximate midpoint of the medial andlateral physis (assuming a non tangential area of the section).

Example 5 Extraction and Quantitation of Chondrogenesis Compounds inJoint and Plasma Rat Samples

LC-MS/MS analysis for Chondrogenesis compounds were performed using anAPI 3000 equipped with an Agilent 1100 HPLC and a Leap Technologiesautosampler. A HPLC Phenomenex 5 micron, 100 A Luna C18 (2) analyticalcolumn with dimensions of 2.0×50 mm (Part No. 00B-4252-B0) at atemperature of 30 C, flow rate of 0.6 mL/min, injection volume of 10 uL,and a 6.0 min run time was used. Mobile phase A1 was 0.1% formic acid inwater and Mobile phase B1 was 0.1% formic acid in acetonitrile. Thegradient was 90% A1/10% B1 at time 0; 90% A1/10% B1 at time 1.0 min; 10%A1/90% B1 at time 2.0 min; 10% A1/90% B1 at time 4.0 min; 90% A1/10% B1at time 4.10 min; 90% A1/10% B1 at time 6.0 min. Analytes and internalstandard quantitation were performed using Multiple Reaction Monitoring(MRM) quantitation method. Listed below are specific methods used todose and measure exposure in plasma and the observed concentration injoint extract.

Rat Plasma Samples:

Calibration standard curve was prepared by serial dilution of aconcentrated, spike solution of the compound in control rat plasma.Calibration standards and rat plasma samples were prepared via proteinprecipitation by adding aliquots of Acetonitrile and internal standardto each aliquot of standards and samples. Following vortex mixing andcentrifugation, aliquots of the supernatants from each standards andsamples were diluted with formic acid in water, mixed and injected. Allplasma samples collected after IA dosing (starting at t=0, 0.5, 1, 2, 4,and 6 h) indicated no systemic exposure for any of the compounds listedin Table 2.

Rat Knee Joint Samples:

Calibration standard curve was prepared by serial dilution of aconcentrated, spike solution of the compound in internal standarddiluents. Internal standard diluent was prepared by dissolving theinternal standard compound at a certain concentration in acetonitrile.Rat knee joint samples for each time points were individually crushedand transferred into each centrifuge tube and added 1.0-mL of internalstandard diluent. Each centrifuge tube was vortexed and centrifuged for30 minutes. From each tube, supernatant was removed and injected ontothe column for analysis. In addition, plasma samples were obtained byretro-orbital bleeds into heparin coated tubes and stored at −80 C andlater processed by analogy to the protocol described above for ratplasma samples.

Compound Administration and Tissue Processing:

30 μL of 100 μM compound solution (PBS with 0.1% DMSO) was injected intothe intra-articular space of the right hinder knee of each animal. Theanimals were euthanized at indicated time points (0 hr, 0.5 hr, 1 hr, 2hr, 4 hr and 6 hr). Four animals were used for each timepoint. Theinjected knee joints were harvested, flash freeze in liquid nitrogen.The whole joints were grounded into powder while frozen, mixed with 1 mLinternal standard-containing acetonitrile, incubated at 4° C. overnight,vortexed and centrifuged for 30 min. The supernatant from each samplewas analyzed using LC-MS/MS. Data shown in Table 2 indicates theobserved concentration in knee extract. ND=Not determined.

TABLE 2 Compound Concentration observed in extract (ng/mL) # T = 0 h T =0.5 h T = 1 h T = 2 h T = 4 h T = 6 h 21 433.5 9.1 4.9 0 ND ND 27 59235.4 6.3 2.5 ND ND 62 411 108.75 52.6 15.7 ND ND 73 587 28.5 9.41 2.6 NDND 113 565.5 25.3 4.2 0 ND ND 117 925.5 50.6 4.4 0 ND ND 123 4430 1102741.25 337.5 38 0 128 7280 2942.5 1365 546 ND ND 156 108.8 3.5 0 0 ND ND

Example 6 Parenteral Composition of a Compound Presented Herein

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound presented herein, or awater soluble pharmaceutically acceptable salt thereof, is dissolved inDMSO and then mixed with 10 ml of 0.9% sterile saline solution. Themixture is incorporated into a dosage unit suitable for administrationby injection.

Example 7 Oral Composition of a Compound Presented Herein

To prepare a pharmaceutical composition for oral delivery, 400 mg of acompound presented herein, and the following ingredients are mixedintimately and pressed into single scored tablets.

Tablet Formulation Quantity per tablet Ingredient mg compound 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Capsule Formulation Quantity per capsule Ingredient mg compound 200lactose spray dried 148 magnesium stearate 2

1.-115. (canceled)
 116. A method of (a) ameliorating arthritis or jointinjury in a mammal, the method comprising administering to a joint ofthe mammal a composition comprising a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt,solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer,or isomer thereof; or (b) inducing differentiation of mesenchymal stemcells into chondrocytes, the method comprising contacting mesenchymalstem cells with a sufficient amount of a compound of Formula I, or apharmaceutically acceptable salt, solvate, polymorph, prodrug, ester,metabolite, N-oxide, stereoisomer, or isomer thereof:

wherein each R¹ is independently halo, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, CN, NO₂,SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴; n is 0, 1, 2, 3, or 4; m is1, 2, 3, or 4; B is CO₂R⁴, CH₂CO₂H, CH₂CO₂R⁴, or optionally substitutedphenyl; Y is a bond, —(CR⁵R⁶)—, —(CR⁷R⁸)(CR⁹R¹⁰)—, or—(CR⁷R⁸)(CR⁹R¹⁰)X—; X is O or CR⁵R⁶; R² is halo, C(O)R⁴, CO₂R⁴,C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, haloalkyl, SO₂R⁴,(CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹¹)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹¹)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; each R³ isindependently selected from H, CN, halo, C(O)R⁴, CO₂H, CO₂R⁴,C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, SO₂R⁴, (CR⁷R⁸)OR⁴,(CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; or R³together with an adjacent R³ or with R² form a ring; each R⁴ isindependently selected from H and optionally substituted alkyl; each R⁵,R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from H, halo,optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and optionallysubstituted alkoxy; and R¹¹ is H, optionally substituted alkyl, C(O)R⁴,C(O)OR⁴, C(O)NR⁴R⁴, or SO₂R⁴; provided that a) if Y is a bond and m is0, then R² is selected from C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,(CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; and R² isnot p-CH₂OR⁴, p-CH₂CH₂OH, or p-CH₂CH₂CH₂OH; and b) the compound is notselected from


117. A method of (a) ameliorating arthritis or joint injury in a mammal,the method comprising administering to a joint of the mammal acomposition comprising a therapeutically effective amount of a compoundof Formula Ib, or a pharmaceutically acceptable salt, solvate,polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomerthereof; or (b) inducing differentiation of mesenchymal stem cells intochondrocytes, the method comprising contacting mesenchymal stem cellswith a sufficient amount of a compound of Formula Ib, or apharmaceutically acceptable salt, solvate, polymorph, prodrug, ester,metabolite, N-oxide, stereoisomer, or isomer thereof:

wherein each R¹ is independently halo, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, CN, NO₂,SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴; n is 0, 1, 2, 3, or 4; B isCO₂R⁴; R² is C(O)NR⁴R¹¹, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,(CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴,X(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; R³ is H; Xis O or CR⁵R⁶; each R⁴ is independently selected from H and optionallysubstituted alkyl; each R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independentlyselected from H, halo, optionally substituted alkyl, OH, NR⁴R¹¹, andoptionally substituted alkoxy; and R¹¹ is H, optionally substitutedalkyl, C(O)R⁴, C(O)OR⁴, C(O)NR⁴R⁴, or SO₂R⁴; provided that if n is 0,then R² is not p-CH₂OR⁴, p-CH₂CH₂OH, or p-CH₂CH₂CH₂OH.
 118. A method of(a) ameliorating arthritis or joint injury in a mammal, the methodcomprising administering to a joint of the mammal a compositioncomprising a therapeutically effective amount of a compound of FormulaIc, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof; or (b)inducing differentiation of mesenchymal stem cells into chondrocytes,the method comprising contacting mesenchymal stem cells with asufficient amount of a compound of Formula Ic, or a pharmaceuticallyacceptable salt, solvate, polymorph, prodrug, ester, metabolite,N-oxide, stereoisomer, or isomer thereof:

wherein each R¹ is independently halo, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted aryloxy, CN, NO₂,SR⁴, S(O)R⁴, SO₂R⁴, NR⁴R¹¹, CO₂H, or CO₂R⁴; n is 0, 1, 2, 3, or 4; m is1, 2, 3, or 4; B is CO₂R⁴; Y is —(CR⁵R⁶)—; C is aryl or heteroaryl; X isO or CR⁵R⁶; R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionallysubstituted alkoxy, haloalkyl, SO₂R⁴, SO₂NH₂, SO₃H, (CR⁷R⁸)OR⁴,(CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹¹)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; each R³ isindependently selected from H, CN, halo, C(O)R⁴, CO₂H, CO₂R⁴,C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, haloalkyl, SO₂R⁴,(CR⁷R⁸)OR⁴, (CR⁷R⁸)NR⁴R¹¹, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴,(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)OR⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)R⁴, X(CR⁷R⁸)(CR⁹R¹⁰)C(O)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴, and C(═NOR⁴)R⁴; or R³together with an adjacent R³ or with R² form a ring; each R⁴ isindependently selected from H and optionally substituted alkyl; each R⁵,R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected from H, halo,optionally substituted alkyl, OH, CO₂R⁴, NR⁴R¹¹, and optionallysubstituted alkoxy; and R¹¹ is H, optionally substituted alkyl, C(O)R⁴,C(O)OR⁴, C(O)NR⁴R⁴, or SO₂R⁴; provided that the compound is not


119. The method of claim 116, wherein: R² is halo, C(O)R⁴, alkyl,optionally substituted alkoxy, haloalkyl, (CR⁷R⁸)OR⁴,(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)C(O)OR⁴, orX(CR⁷R⁸)C(O)NR⁴R¹¹; and each R³ is independently selected from CN, halo,C(O)R⁴, CO₂H, C(O)NR⁴R¹¹, alkyl, or optionally substituted alkoxy; or R³together with an adjacent R³ or with R² form a ring.
 120. The method ofclaim 119, wherein: R² is F, Cl, C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr,OCF₃, OCHF₂, (CR⁷R⁸)OR⁴, (CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and each R³ is independentlyselected from CN, F, Cl, C(O)CH₃, CO₂H, C(O)NH₂, CH₃, OCF₃, or OCH₃; orR³ together with an adjacent R³ or with R² form a ring.
 121. The methodof claim 120 wherein R² is F, Cl, C(O)CH₃, CH₃, CF₃, OCH₃, OEt, OPr,OCF₃, OCHF₂, CH₂OCH₃, CH₂OH, CH₂CH₂OH, CHOHCH₂OH, CH₂CH₂CH₂OH,CH₂CHOHCH₂OH, OCH₂C(O)OH, or OCH₂C(O)NH₂.
 122. The method of claim 121,wherein each R³ is independently selected from CN, F, Cl, C(O)CH₃, orCO₂H.
 123. The method of claim 116, wherein: R² is (CR⁷R⁸)(CR⁹R¹⁰)OR⁴,X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹, (CR⁷R⁸)C(O)R⁴,(CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹, (CR⁷R⁸)NR⁴SO₂R⁴,or C(═NOR⁴)R⁴; and R³ is H.
 124. The method of claim 117, wherein: R² is(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)OR⁴, X(CR⁷R⁸)(CR⁹R¹⁰)NR⁴R¹¹,(CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)R⁴, X(CR⁷R⁸)C(O)NR⁴R¹¹,(CR⁷R⁸)NR⁴SO₂R⁴, or C(═NOR⁴)R⁴; and R³ is H.
 125. The method of claim118, wherein C is aryl.
 126. The method of claim 125, wherein C isphenyl.
 127. The method of claim 118, wherein C is heteroaryl.
 128. Themethod of claim 127, wherein C is pyridinyl, pyrimidinyl, pyridazinyl,or pyrazinyl.
 129. The method of claim 116, wherein: R² is halo, C(O)R⁴,CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionally substituted alkoxy, haloalkyl,SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴, (CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹,X(CR⁷R⁸)C(O)OR⁴, or X(CR⁷R⁸)C(O)NR⁴R¹¹; and each R³ is independentlyselected from H, CN, halo, CO₂H, or haloalkyl.
 130. The method of claim118, wherein: R² is halo, C(O)R⁴, CO₂R⁴, C(O)NR⁴R¹¹, alkyl, optionallysubstituted alkoxy, haloalkyl, SO₂NH₂, SO₃H, (CR⁷R⁸)C(O)R⁴,(CR⁷R⁸)C(O)OR⁴, (CR⁷R⁸)C(O)NR⁴R¹¹, X(CR⁷R⁸)C(O)OR⁴, orX(CR⁷R⁸)C(O)NR⁴R¹¹; and each R³ is independently selected from H, CN,halo, CO₂H, or haloalkyl.
 131. The method of claim 116, wherein B isCO₂R⁴ and R⁴ is optionally substituted alkyl.
 132. The method of claim117, wherein B is CO₂R⁴ and R⁴ is optionally substituted alkyl.
 133. Themethod of claim 118, wherein B is CO₂R⁴ and R⁴ is optionally substitutedalkyl.
 134. The method of claim 116, wherein B is CO₂R⁴ and R⁴ ishydrogen.
 135. The method of claim 117, wherein B is CO₂R⁴ and R⁴ ishydrogen.
 136. The method of claim 118, wherein B is CO₂R⁴ and R⁴ ishydrogen.
 137. The method of claim 116, wherein n is 0, 1, or
 2. 138.The method of claim 137, wherein R¹ is independently selected from Cl,F, CH₂OH, CH₂NH₂, OCH₃, OCF₃, OCHF₂, CN, NO₂, CO₂H, and CO₂CH₃.
 139. Themethod of claim 117, wherein n is 0, 1, or
 2. 140. The method of claim139, wherein R¹ is independently selected from Cl, F, CH₂OH, CH₂NH₂,OCH₃, OCF₃, OCHF₂, CN, NO₂, CO₂H, and CO₂CH₃.
 141. The method of claim118, wherein n is 0, 1, or
 2. 142. The method of claim 141, wherein R¹is independently selected from Cl, F, CH₂OH, CH₂NH₂, OCH₃, OCF₃, OCHF₂,CN, NO₂, CO₂H, and CO₂CH₃.
 143. The method of claim 116, wherein thecompound is selected from

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.
 144. Amethod of (a) ameliorating arthritis or joint injury in a mammal, themethod comprising administering to a joint of the mammal a compositioncomprising a therapeutically effective amount of a compound; or (b)inducing differentiation of mesenchymal stem cells into chondrocytes,the method comprising contacting mesenchymal stem cells with asufficient amount of the compound, wherein the compound is selected from

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.
 145. Themethod of claim 116, wherein the mammal is a human, a dog, a cat, or ahorse.
 146. The method of claim 117, wherein the mammal is a human, adog, a cat, or a horse.
 147. The method of claim 118, wherein the mammalis a human, a dog, a cat, or a horse.
 148. The method of claim 144,wherein the mammal is a human, a dog, a cat, or a horse.
 149. A compoundselected from

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug,ester, metabolite, N-oxide, stereoisomer, or isomer thereof.
 150. Apharmaceutical composition comprising a compound of claim 149, or apharmaceutically acceptable salt, solvate, polymorph, prodrug, ester,metabolite, N-oxide, stereoisomer, or isomer thereof, and apharmaceutically acceptable excipient.
 151. A pharmaceutical compositionof claim 150, further comprising an additional compound which istherapeutically effective for the treatment of arthritis or joint injuryand/or the symptoms associated with arthritis or joint injury in amammal.
 152. The pharmaceutical composition of claim 151, wherein theadditional compound is selected from NSAIDS, analgesics,angiopoietin-like 3 protein (ANGPTL3) or chondrogenic variant thereof,oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3(choliecalciferol), collagen hydrolysate, FGF18, BMP7, avocado soyunsaponifiables (ASU), and hyaluronic acid.